Thanks, everyone, for joining. This is the Fireside Chat with Kymera Therapeutics. Happy to have with me Nello and Jared from Kymera. Thanks so much for joining us. Appreciate it.
Thanks, Vikram.
Yeah, thank you.
Before we get started, I need to read this disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, let's dive into it. Nello, good to have you here, both of you. Quite a lot to talk about in the pipeline and with your different therapeutic area focuses versus in I&I versus oncology. Maybe the best place to start is just kind of at a high level, some opening remarks from you on where you've been focused for the business, what you think some of the key milestones have been for the year, and where you think people should be focused when they think about Kymera, kind of over the next twelve months or so.
Yeah. So I mean, let me start just by reminding everybody. So Kymera was founded with the vision to building a fully integrated biotech company that will use a technology like targeted protein degradation to develop a new generation of medicines, to address targets and diseases that have not been addressed by other technologies. And so we have been totally focused in the past eight years to identify the type of clinical problem, the type of target that we believe is perfectly suited to use targeted protein degradation for and deliver really groundbreaking medicines and not just incremental improvements over existing therapies.
So, maybe just to remind briefly to everybody, targeted protein degradation allows you to use small molecules to degrade disease-causing proteins, and by degrading, I mean eliminating disease-causing proteins from their cellular localization in a completely specific and selective manner. So it's really groundbreaking opportunities to go after proteins that are not addressable by, let's say, monoclonal antibodies, because they're in the cell, or by small molecule inhibitors because they don't have a catalytic site that a small molecule inhibitor can get to. So I think it's important. I know this is probably more common knowledge these days, but I feel it's important to remind everybody that we have a unique opportunity to choose to use this technology to go after really difficult-to-drug or undrugged targets to unlock new, a new space in terms of clinical and commercial opportunities.
So what have we done in this space? We've been using, to be honest, target selection as our North Star. Our North Star has been working in pathways that have been validated, where there is human pharmacology, where ideally there is human genetics, but going after, again, nodes in those pathways that have not been drugged or drugged well with other modality, where protein degradation is the unique technical solution, and especially in the past few years, focused on areas with broad potential, both clinical and commercial. What we're most proud of in the past few years has been our ability to translate our preclinical profiles into the clinic. We've taken four programs into the clinic across oncology and immunology, and we've shown exceptional translation of PK with fidelity, of PK, PD, safety, and early efficacy.
One thing that we're also proud of, because not only it's something that we've done first, but actually has opened up our path into immunology, has been, you know, taking the first program in the clinic in immunology. So we've learned what it takes to build immunology drugs, what is the regulatory path to de-risk their development, what are the features and the work that we have to do for those molecules to be selective active and broadly active against different cell types. So with IRAK4, we've shown, for example, we integrate in the blood and skin, have impact in biomarkers, and then and finally have impact on disease states in both HS and AD.
So going in the next twelve months, what we shared early in the year is our increased commitment to immunology. We've unveiled two new programs, a STAT6 degrader that we like to call dupilumab-in-a-pill. We've also disclosed our TYK2 degrader, which we believe has the potential to have biologics-like activity. And we said that this is the area where we're going to spend most of our time and money in the next few years. We are just about to enter the clinic with our STAT6 degrader. And so next year, we'll have phase I healthy volunteer data, and potentially data in patients as well. We'll address that as we get closer.
With our TYK2 degrader, we should be in the clinic in the first half of the year, with healthy volunteer data in the second half of the year. We have recently disclosed that Sanofi has expanded and extended our current phase II studies in order to accelerate overall development timelines in both HS and AD. So in the next few weeks, we'll be able to add more color on timing and size of trials, et cetera. We have upcoming data readouts in oncologies. And one thing that I also want to say, and I'm sorry, I'm taking way too long-
No worries.
Luckily, we have 40 minutes, so we got plenty.
Thirty-five , but that's fine.
Thirty-five. All right, I got that wrong, too. I think one thing that I also want to make sure it's well understood is our commitment to continue innovation and our commitment to build a company that can deliver innovation over and over again. This will continue to be there and will be, you know, viewed as we continue to disclose new programs that are going in the clinic in the next few years. One probably starting from next year already.
Got it. Okay, great. Helpful way to level set on a couple of different fronts. Let me ask you kind of a big picture question back. It seems like the number of biotech companies, the number of biopharma companies nominating degraders into their pipeline is growing over time. I mean, given your experience in this space, what do you think a company needs to have in place to be able to prosecute degraders successfully through early to mid-stage development, at the very least?
Yeah, so first, I would agree with you that targeted protein degradation is a must-have technology in a toolbox of a serious biopharma company. It's just that's a fact. And I think companies, most companies that I'm aware of have either attempted doing it or doing in partnership. I think what has killed, over the years, the early attempts of especially larger companies into innovation and innovative space like protein degradation, and you can go back and look at what happened in RNA interference history, you can look at ADCs, you can look at CRISPR.
There is that initial enthusiasm of everybody's now working on this particular area before realizing the level of commitment, going to your question, needed to be a credible player in the space, meaning the commitment, the focus that is needed to master a new technology. I'm not. I personally do not believe that targeted protein degradation is a commoditized technology, and I believe that it has a low barrier to entry, but a high bar for success, and I think companies that are doing well are very, very few.
Understood. And there's also a little bit of concentration around similar targets across certain pipelines, right? What do you think drives that?
I think Kymera drives a lot of that. I think if you look at our pipeline, we were the first with an IRAK4 degrader. Now, there is at least another couple of companies. We are the first with the STAT3 agent, selective agent. There is a few companies that followed us. From what I hear, everybody's working on STAT6 these days. At least whenever I walk down the road, that's what I'm told by everybody. So I think there are innovators and there are followers, and that happens every time. And that's actually a sign of you know how much need there still is for like true innovation in biopharma.
And it's also true that if you have something that works, there's always the idea I can do it, and I can do it better. And that's not only true for protein degraders. Look at how many CD19 programs and how many PD-1s the industry has gone through. I mean, our industry is amazing for building inefficiencies, so I'm not surprised that we're also doing it in this space.
Fair enough. Fair enough. Okay.
Am I being too critical?
No, completely fine. Also a good segue into my next question around the stronger focus you placed for Kymera on I&I, starting, I think, this past January through your R&D Day. How is that pivot progressing? And taking a step back, what prompted that shift in emphasis?
Yeah. Yeah, let me not correct, but, but refine your statement. So our external articulation of our increased focus happened in January. Our increased focus in immunology goes all the way back to, I would say, late 2019, early 2020. And that's actually the year in which we made a concerted effort to shift a lot of our resources into immunology. And so what's driven that? A series of factors. One may be the most important one, has been our early success with IRAK4. Our ability to translate exceptionally well the PK/PD that we've seen in preclinical with IRAK4 into healthy volunteers.
It was the first time that that had been done, and I think while now seems an obvious path that we took, it wasn't done, you know, without being, you know, nervous about the early outcome, or at least aware of how important it would be. And so that gave us the confidence to say, you know, protein degraders can work really well outside of oncology, which, you know, before had been, and actually made us appreciate even more and do a bit of a deep dive into, now that we know that we can do it, what are the key pathways and targets that we can unlock and become, you know, a real powerhouse in immunology.
We found that in front of us, opportunities like STAT6, like TYK2, like others that you'll hear about in the next few months, that I believe are these once-in-a-generation opportunities of having oral drugs with biologics-like profiles. We believe that degraders are uniquely positioned to give you both the efficacy, and if you pick the right target, the safety of a biologics. We can change the paradigm of the industry. If you talk to commercial consultant companies, the reflex is, you know, you're going to compromise on efficacy with an oral drug because that's the perceived notion. I think what we're trying to change the narrative is, with data, is actually, no, with degraders, you don't have to compromise on efficacy. You can have biologics like activity in oral drugs, and that's really what has been the driver behind everything that we've been doing and we're continuing to do.
Understood. Great. I guess let's just kind of build on the INI theme then. 474 , you mentioned that there was recently a decision by your partner, Sanofi, to expand the phase II program. Could you unpack for us kind of what drove that decision, what data you've seen from the program so far, what data they saw to inform that decision, and how the scope of the phase II could change based on that?
Yeah, I mean, good thing we all looked at the same data. So, what we have underpinning the strategy was really exciting early data from Kymera, showing really robust degradation in blood and skin, and early proof of concept, you know, you can call it, in both HS and AD. That I think both companies felt was impressive early data, exciting early data, encouraging early data. So I think what happened recently, it's you know what happens in drug development where you know you have an ongoing, let's call it, proof of concept study in HS and AD. I think you realize that there is an opportunity to accelerate, because you know I think the time is now for oral drugs and immunology. I believe Sanofi agrees.
The opportunity was instead of doing a proof of concept and a dose-ranging study to actually combine the two into a single seamless study. In order to make this transition, Sanofi you know elected to look at interim safety and efficacy to make it a data-driven decision. I can't go into what was seen or not seen, but I can say that what was seen gave Sanofi and us, obviously, they're driving the program, the confidence that the increased investment is worthy and that of the program, and that you know now is the time to expand the study. The expansion of the study is really focused on adding more doses, which is a regulatory requirement to then transition into a phase III study.
The main difference besides the, you know, the additional doses and patients that we'll see on ClinicalTrials.gov in a few weeks, I believe, is also that obviously the timeline of the actual phase II study will be extended because it's extended the study, but the overall timelines have been decreased substantially, and hopefully, when the ClinicalTrials.gov posting will go live, the new one, we, you know, there'll be new completion dates, and we can talk about the new timelines to data now of this expanded study.
Got it. Got it. Okay. I recall that you previously outlined a pretty big indication set where 474 could go, within the I&I space. What, what do you and Sanofi need to see to make a decision on where else to go besides HS and AD? Is it necessarily dependent on data, like the next cut of data from these two indications, or are these discussions kind of ongoing right now?
Yeah, I mean, look, this is always a tough question for me to answer because we have a very good relationship with Sanofi, where they've been great partners over the years, and they allow us to have a seat at the table, and Jared, actually, and his team are at that table, to decide and discuss and prioritize indications. That has gone well, and as I've said in the past, we have a clear plan for what those are, which is, you know, they're actually quite obvious indications, for this pathway. I think what is not being fully fleshed out is when the next study will start, and I'm just gonna let Sanofi comment on that, not to get in trouble once again.
Fair enough. You also have an opt-in on this molecule, right?
Yeah.
That you can exercise at some point. Talk us through kind of how exactly that opt-in works and when might be a good time for you to make a decision around that?
Yeah, I thought when we signed this deal, this was a very clever approach that we took to say. You know, we were back then an early company with limited resources, and we said, you know, we transitioned the program to Sanofi, but in the presence of outstanding data, and remember, this was, you know, it still is a big program for us. We wanna have an opportunity to own 50/50 the U.S. market. And instead of having to make that decision early in development, which is happening in many of the more recent deals that I've seen, we were fortunate enough, maybe good enough, to get the deal done in a way that we can actually make the decision after we see phase II data and right before a phase III campaign is being started.
So, you know, that timeline is still there, and, you know, we have an opportunity to look at data and make that decision. Maybe one thing I wanna clarify for everybody, the opt-in is into the global development program. It's not indication by indication. So once we opt in, we're in across all the potential future indications.
Got it. So that would be... You'd be opting in for all the indications that have been nominated to that point?
And futures.
And anything in the future.
Anything, the whole global program.
Got it. Okay, great. That's helpful. Can we pivot to 621 and 294 then?
Sure.
I think everyone might appreciate kind of your guidance on how best to interpret the initial phase I readouts for those molecules coming next year, and maybe also a bit of color on kind of what you've seen preclinically to give you conviction that this was the right direction to go in.
Yeah. So, let me take the second, and I'll let Jared kind of talk about the clinical studies. I've rarely seen, if ever, you know, a preclinical profile of a molecule that has such a robust data set in terms of PD efficacy across a plethora of systems, in vitro, in human systems, in all species that we looked at. So I think what we were able to demonstrate is that if you degrade STAT6, you're able to block IL-4 and IL-13 signaling completely, and you're able to phenocopy, in terms of pathway engagement, what an upstream biologic can do, and especially what an IL-4 receptor alpha, like Dupilumab, can do. And that is, I believe, again, the first time that it's been shown, even with just preclinical data, that you have an oral molecule that can basically match the ability of a biologics to block that pathway.
We're going into the clinic with the excitement of really translating that profile into humans first, into healthy, and then into disease patients. And to be honest, our bar is to have this Dupixent molecule in an oral pill that we believe has the opportunity to change the treatment paradigm. Maybe we'll get to that in a second, then Jared can speak to maybe our phase I.
Yeah, so in terms of the design, you know, our phase I healthy volunteer study is a SAD/MAD, so not dissimilar from what we did for IRAK4, KT-474. The MAD portion will be 14 daily doses. I mean, really, our primary objective of this study is to show that we can fully degrade IRAK4, excuse me, STAT6, in blood and in skin. So in the MAD portion, we'll be looking at STAT6 in both blood and skin, and the SAD just in blood.
But I think it's very important for us to sort of reach that objective, 'cause we know from our preclinical work in some of these workhorse disease models of AD and of asthma, we've shown that we can reach Dupixent-like activity or even activity that sometimes is even superior to Dupixent in these models when we degrade STAT6 by at least 90%. And we believe we can achieve that sort of degradation, even beyond 90%, in the clinic fairly readily with the doses we plan to interrogate in phase I. So I think the aim is to show that level of degradation, 90% or greater, in blood and in skin, show acceptable safety, predictable PK, and we also have the opportunity to look at some Th2 biomarkers.
'Cause even in healthy volunteers, there's some low level of Th2 tone, and you can look at biomarkers like TARC and IgE. It's been shown, for example, Regeneron has shown with Dupixent in healthy volunteers, that you can see modest 20% or so reductions in IgE, 30%-40% reductions in TARC, with Dupixent in healthies. And so we think we can use these as exploratory biomarkers in phase I to show similar levels of modulation, with our STAT six degrader, 621 , to go along with showing, you know, using very quantitative PD assays, this robust degradation of STAT6 in blood and skin, and very importantly, to show the safety that is gonna allow us to really de-risk the program for the next step, which is then moving rapidly from healthy volunteers into patients.
Got it. Got it. At what point do you start thinking about the right indications to move into, and what helps kind of guide you on that decision process? Is it purely just what you're seeing in the phase I readouts next year? Is it also kind of a consideration of commercial opportunity? Kind of what. How is that going to unfold?
You know, look, I can start. You know, essentially, we're following sort of the Dupixent blueprint, right? Essentially, we can take a look at the various indications where Dupixent has been active and is approved, and those are certainly indications where we feel our drug should go, if it's capable of having activity comparable to Dupixent, which we believe it is, and having safety that's comparable as well.
I think we're very interested in starting off with the larger indications, so I think indications like AD, asthma, and COPD, not necessarily prosecuting them all at the same time. But I think it is important for us to sort of get to these indications as quickly as possible. So I think starting with the larger indications, and then moving on to the other indications that may be smaller, but that are still indications that are important, where we think we can have transformative activity.
Got it. Got it.
Yeah, I think maybe just to add one comment. T hanks, Jared, our focus is to do, obviously, a rational, data-driven development path, but the overarching themes, I guess, there are two. One is, how quickly can we get to phase III, and how broadly can we address, especially the large indications? And I think, you know, for people that have seen under CDA, our development plans, I think we strongly believe that this is as competitive as you can be with anyone, with anybody, with, you know, any type of resources to do it right.
Got it. Is it fair to say that indication selection, at least for the first round of indications for both molecules, sounds like it could be a 2025 decision, at least internally, for you?
I mean, I think we've already... Like, assuming that the program translates as we expect and hope, those decisions have all been made already.
Okay.
What we've decided to do is just not to talk about our plans, just because as we just discussed, there is a lot of following out there. So I don't think we need to, you know, share with people, unless, you know, it, it's material for our investors, and then obviously, we'll make sure everybody's aware of what we're doing. But we don't have to do that so much ahead of time.
Got it. So I'll reframe the question then. So I guess, it's the public disclosure of the indications in the next year?
The public disclosures of indications, type of studies, sequence of studies, will happen as we continue to advance the program, starting from 2025.
Fair. Fair. Okay, great. I guess final question then on these two programs, and then we'll move on to other items in the pipeline. Given, you know, you've mentioned some of these indications could be sizable, therefore, some of these studies could be sizable, do you feel the need to involve a large biopharma partner for either or both of these programs anytime in the near future?
So, you know, we actually, you know, recently completed another relatively small financing. So we have about $930 million in our bank, which is both a lot and a little, depending on your plans. But we are well-financed to run many, many studies that will get us through key inflection points, including those ranging studies in important indications. So, we don't believe that actually it would be either value add or will reduce timelines if we engage other parties between now and phase III.
I think once we are planning phase III studies, hopefully, we will relatively soon, and depending on what the world will look like, our access to capital, our cost of capital, our opportunities in front of us, decisions will be made about what is the best path to value creation. What we're trying to do as a company is to give us the optionality to make the decision of what's right for the company and for the program, and not what we must do because we either ran out of money or because we made the wrong decision.
Right.
Conserving optionality as much as possible, and then make a data-driven decision, both scientific data and any other data that can influence those decisions.
Understood.
So no partnerships in immunology for the foreseeable future, we're talking about for the next few years.
Got it. Okay. So given this stronger emphasis in recent times on I&I, what is your internal threshold now for investing more dollars into oncology, either new programs or the existing programs for STAT-3 and MDM-2?
So our threshold bar is, you know, has been clarified, I would say. We've always had a bar, but I think the past couple of years have given us an opportunity to really set that bar very clearly. And so in order for us to invest, both now pre-clinically and clinically, we have to fulfill the criteria of, you know, not only the target selection, but we need to fill the criteria of a clear path to a proof of mechanism, proof of concept that shows that the drug is best in that particular pathway or mechanism, and that we have large addressable populations that are measured by hundreds of thousands, if not more, and not by hundreds or thousands of patients.
With that in mind, I think you should expect that whether it's in oncology and immunology, programs where we have limited patient impact will probably be pursued, likely in partnership. Programs that we believe have broader opportunity set, we're gonna try and retain for as long as possible, and ideally, in some cases, all the way through. One other thing that I would say is that our discovery engine is not only focused on oncology and immunology. I would say that immunology is probably now 80% of what we do, both now in terms of resource spend, as well as type of targets that we're focused on. But we always believe that degradation is a disease-agnostic technology, and I think our capabilities are definitely disease agnostic, at least preclinical.
Right now, we're building lots of immunology capabilities in terms clinically. But, you know, there are areas that are now ripe for the technology, areas that have become now extremely large addressable population in, you know, cardiovascular and obesity and those spaces. So obviously, you should expect us spending time in that, in that space as well. Nothing that we'll disclose probably in the next couple of years, but that's definitely an area that we're interested in.
Got it. Got it. I guess on the point of broader R&D productivity, what should people look for in terms of, the cadence with which you'll nominate new pipeline programs, whether that's I&I, oncology or something else?
Yeah. I think at least one new IND per year. You should expect one new program per year. Last year, we had two programs, and I believe the year before, we didn't disclose one, so we're still on the same track. Next year, we'll have at least one program, maybe two, and the following year, the same. So, that's the cadence that we should expect, and as long as we continue to execute, we don't foresee that being less in the future.
Understood. Okay. In the last couple of minutes left, maybe we should talk a little bit about the catalyst path for the oncology part of the pipeline. So, maybe we'll start with 333 . Jared, over to you. I guess, what's the most, I guess, recent data cut you've seen there, and what are some of the next steps, and what should people look for in the balance of the year?
Yeah, the most recent data cut was back in June at the EHA meeting for STAT3. I think there we showed, I think, very robust knockdown of STAT3 in blood and in tumor at doses that were well tolerated. We actually have completed dose escalation without having reached an MTD, but we really came up with a recommended phase II dose, really based on having maxed out on knockdown in both blood and tumor. We saw, we thought, you know, fairly remarkable responses in lymphoma, including cutaneous T-cell lymphoma, and especially Hodgkin's lymphoma, where we saw several complete responses with those patients going on to hopefully curative transplant.
So, you know, our aim for the rest of the year is to enroll additional Hodgkin's patients, you know, multiply relapsed Hodgkin's patients onto the study, try to get a better sense for overall response rate and tolerability among those patients. And then later in the year, probably at a medical meeting, perhaps at ASH to provide sort of a final update on the study in terms of final sort of PD and safety, you know, for the program, the sorts of responses that we're seeing in Hodgkin's, and then provide guidance on potential next steps. You know, as Nello alluded earlier, those next steps might involve, a partner, especially if it's potentially development in Hodgkin's lymphoma, either as a monotherapy in the third line or as a combo PD-1 combo in second line or greater. So that's what to expect for 333 .
Got it. And a similar question for MDM2. Kind of where do you see that program going? What's the right patient population to think about there?
Yeah, I think MDM-2, you know, we also gave an update at ASCO in this past June. You know, we've actually, with MDM-2, we have two different arms. We have a lymphoma, solid tumor arm, and we have an AML arm. We've actually shown very nice on-target pharmacology, you know, at doses that are well-tolerated and not showing the usual toxicity that you see with MDM-2 small molecule inhibitors, like myelotoxicity. We've actually seen clinical responses in both solid tumors as well as in hard-to-treat AML subsets. So what we're doing for the rest of the year is continuing to dose escalate.
It's possible we might complete dose escalation by end of the year, but it's also possible that might continue if our safety profile is still favorable, in which case, if we're continuing, we may wait until sometime early next year before we present the next update on the program clinically. I think we have a large effort, you know, pre-clinically aimed at trying to identify solid tumor patient populations, in particular, who may be very sensitive to this approach, trying to identify biomarkers of sensitivity.
We're planning on presenting those data at probably at the Triple Meeting later this fall, so that will give folks their first opportunity to see all the work that's been done to try to identify patient populations who are more sensitive to the drug. That might help us enrich for those patients, not just for the remainder of phase I-A, but also as we move beyond phase I-A into the next stage of development.
Got it. Got it, great. I guess a final kind of catch-all question for you. You mentioned different disease verticals where the platform could be used, and I know you're not providing specific guidance now, but what are some other logical areas where the Kymera platform could be useful, whether that's cardiovascular, neurology? Just what's a natural fit t he way your platform's kind of been designed.
Yeah. I would say maybe let's just stick with immunology a bit, just to give a bit of a better sense of what areas we're interested in, right? We've shown. So Th1, Th17 with IRAK4, probably likely the best Th2 drug with STAT6, IL-23, type I interferon with TYK2. You'll see another target next year in a contiguous complementary area in rheumatology. A couple of other areas of high interest for us are kind of immune system resetting, again, with oral drug and autoantibody-driven diseases with oral drugs. I think with these six pillars, the idea will be to have, if not the best immunology pipeline in industry, at least the best oral immunology pipeline in industry, with potential to combine also, which is something we're already working very actively on, not clinically.
So that's important. That I think is an important piece of information to think about what's coming ahead. Again, as I said, outside, you know, there is areas of neuroinflammations that are interesting. I think now that, you know, obesity has been characterized as a disease with validated pathways, I think it's perfectly suitable for oral degraders. I think that would be another area of interest. And, you know, there's still opportunities for, you know, genomically defined diseases that I think degrader could work really well. So, you know, I think some of these will take a bit longer to be fully fleshed out and communicated, but time will tell.
Got it. No, helpful context. Final housekeeping question for you, maybe one for Bruce. You mentioned $900 million in cash at was your most recently reported cash balance. In terms of runway that provides, the level of pipeline development that contemplates, kind of where does that get you and where d oes it get the programs?
So 9:30 will get us now into mid-2027 a s opposed to before, which we're in early part of 2027. Importantly, actually allows us to have many inflection points across many of our programs. Obviously, IRAK4 with 474, actually multiple data readouts, both in healthy and multiple data readouts in patients. TYK2, the same, as well as novel programs in the clinic. So we're positioned to create value, and to actually not having the pressure of financing, you know, for the next data readout that we have.
Got it. Great. With that, we'll close out. Nello, Jared, thanks so much for joining us.
Thank you.
We appreciate it. Thanks, everyone.