Good afternoon, ladies and gentlemen, and welcome to the 45th Annual Goldman Sachs Healthcare Conference here in Miami. Pleased to present to you Kymera Therapeutics. On stage with me is Nello Mainolfi, President and CEO.
Thank you. Thanks for the invite.
Absolutely. Glad to have you here. I think to kind of level set and start the conversation, if we could start by understanding the targeted protein degradation space a little bit more, could you give us an overview of your technology and approach, and how protein degraders differ from more perhaps conventional approaches?
Yeah, so great question. So first, just to also level set, so Kymera, obviously a company that has been working in protein degradation for the past eight years, their focus is really to use this novel, potentially transformative technology to change treatment paradigms across different disease types. And what does protein degradation do? How can this technology unlock value? It's really the coming together of two unique opportunities. One, the power of genetic-like knockdown with the simplicity and ease of development of small molecules. So the technology is, at the high level, quite simple. You use heterobifunctional molecules, so bispecific molecules. They're able to bind a protein that you want to degrade, that you want to remove, a disease-causing protein. At the same time, an E3 ligase, which is a protein part of the cellular machinery that is responsible for eliminating bad protein, the ubiquitin proteasome system.
So by binding at the same time to a target protein and this E3 ligase, we're able to bring disease-causing protein to proteasomal degradation and elimination. So for the first time, actually, ever, you can now target, remove a disease-causing protein from its site of action with a small molecule.
No, that was great. Could you speak a little bit more to how your approach to target selection works, especially given the fact that you've had kind of a shift in terms of the focus strategically for the company, moving from oncology versus now the new prioritization of I&I more broadly?
Well, our strategy has actually been consistent with identifying targets that have not been drugged or drugged well before within pathways that have been highly validated, ideally with human genetics data for that particular target, where protein degradation is the only or best solution to target that particular both disease pathway and target. And I think what our focus has been and will continue to be even more in targets that can unlock large patient populations, and with that, obviously access large commercial opportunities.
I mean, what we've discussed in January are enhanced focus in immunology, but I will also remind everybody our first program was a program in immunology with IRAK4, a program we brought to the clinic in 2020, and a program from which we've learned a tremendous amount of knowledge with regards to how to best design a degrader for immunology, how to develop it, how to make sure that we have predictable PK/PD safety and activity. And from that program, we were inspired by the fact that you can now, if you select the right pathway and the right target, build degraders that can match biologics activity. And that's really our enhanced focus in immunology being driven by the concept of biologics like with a simple oral drug.
I would say that as part of our strategy, we've been also in pathways that have relevance in oncology, and that is still an area that we're generating exciting data. We had data at ASCO a couple of weeks ago. We had data at EHA this weekend, and continues to be an area where we believe we can demonstrate the power of the technology and also the impact on patients.
Digging a little bit more into specific assets, let's shift gears a little bit towards KT-474, your IRAK4 degrader. Great segue there. First, if you could kind of walk us through your clinical proof of concept data that you saw in the phase one, help put the data in context relative to the standard of care.
Yeah, so I will just go back quickly. So why is IRAK4 degradation both an interesting target and the right technology? So IRAK4, interesting target, and degradation, the right technology. So the IL-1R pathway in which IRAK4 is a central node has been extensively validated across a variety of immune inflammatory diseases, meaning that drugs that target upstream cytokines like IL-1 alpha beta 18, 33, 36, so monoclonal antibodies that target those cytokines have shown activity in these diseases: HS, AD, RA, asthma, et cetera. So the holy grail in that pathway has always been the intracellular node that would allow not only to have an oral drug, but also a drug that will have the theoretical combined activity of the upstream biologics.
That's really what an IRAK4 degrader can do, that by removing the protein altogether, both the kinase and scaffolding function, we are able to block the pathway fully and actually technically being able to develop an asset that has a depth of clinical activity that is expected to be superior than the upstream biologics, individual biologics. So the data we've shown, sorry for the long preamble, the data that we've shown in close to 200 patients' worth of data between healthy volunteers, HS, and AD patients, that KT-474 is a very active degrader. It degrades the protein all the way to complete removal of IRAK4 in blood of healthy volunteers as well as of patients with HS and AD. We also have robust degradation in the skin. We can impact cytokines and chemokines that are downstream of IRAK4 in both healthy volunteers and patients in blood and skin.
And all this characterization has also led to, after a short study, 28-day study, has led to patient impact in both HS and AD patients in both symptoms and scores of HS and AD. We have data after only 28 days of dosing that we believe are compelling, although early, and not dissimilar from approved agents in those diseases. Now, I think the goal of our ongoing phase 2 studies is obviously to dose longer and characterize clearly the clinical activity of this drug.
How are you and your partner, Sanofi, thinking about how and where this oral agent could perhaps fit in the treatment algorithm, and how is that influencing your later stage trial design strategy?
Yeah, so first I should say that we have been obviously running this program from inception all the way through end of phase one. We partnered with Sanofi just before we entered the clinic, and now the program is in their hands, and they are responsible for execution of phase two and beyond. So there is only so much I can speak because I cannot speak for Sanofi, but what I can say, the opportunity with IRAK4 is to provide an active and well-tolerated oral daily drug that could be potentially positioned as early line therapy for a broad set of patients before potentially patients have to then eventually move into a more expensive biologic. So I believe there is a unique opportunity that the IRAK4 mechanism has in HS, AD, but in many other diseases where this pathway is shown to be relevant.
We can imagine, given the data that is out there, that this pathway could be relevant in asthma, in COPD, in IBD, in lupus. So the opportunities are vast. Obviously, we're taking this in a stepwise fashion, and the first two diseases that we're going after is collaboration on HS and AD.
For dosing, you've talked about responses that could deepen over time with chronic dosing. What have you learned about the kinetics of your drug so far? What can you expect based on the phase 1 experience, and how do these compare to the standard of care of other drugs in development?
Yeah, so there are two aspects to the question. One is, and then the other one is kinetics of response. And I just want to separate the two. Kinetics of degradation, it takes us about 7 days to reach steady state in terms of degradation in blood, which means that we reach maximal and then maintained level of degradation by day 7, which is obviously the nice thing about small molecule oral drugs that you can have time of action that could be quite fast. In terms of what is the kinetics of response, it's something that we yet don't know, right? We've only run a 28-day study where we've seen already, we believe, encouraging and robust activity.
Now, again, the study was small and without placebo, so I encourage everybody not to actually read the exact numbers, but I think if you look at the trends and the totality of the data, you definitely see an effect that will be quite unlikely to be driven by placebo. So now what we're doing in this 6-week study is to establish what is the kinetics of disease impact. We know that at 28 days, although in a small study, we see an effect, and I think it will be exciting to see what we see after much more prolonged effect. And what is the nadir of maximal effect? I think it'll be interesting to see, and we'll continue to monitor this. There'll be a 16-week study. As we go later in development, there'll be opportunity to follow patients well beyond 16 weeks.
I think time will tell us where is the maximal patient benefit.
Timing. I am going to slightly push my luck just a little bit here, but you have mentioned that data from both studies will be coming likely in 1H 2025, atopic derm in January and HS estimated to complete in February of 2025. Could these data come potentially at the same time? Help us perhaps understand what we'll learn about the results. Would you expect that you and Sanofi will be able to send out a press release with top-line results with details at a specific medical meeting? What's kind of the goal here?
Yeah, so there's a lot that I cannot say, especially because it's still early with regards to the end date of the completion of the program. But so first, what I will say is in terms of timing, we've said publicly both Sanofi and Kymera independently that data are expected in the first half of 2025, and obviously that still continues to be the guidance, so we're still on track for that. With regards to how the data will be communicated, it's too early for me to comment on. I assume that there will be a combination of press releases and presentation at medical meetings, but it's early to say which meetings and when exactly.
Right, makes sense. I guess moving a little bit further into your pipeline, so you have KT-621, which is your STAT6 degrader. Could you give us an overview of this program, which is set to enter the clinic second half of this year? How does the preclinical data in mice and non-human primates look from a PK and safety perspective? What are perhaps the rate-limiting steps to getting this into patients?
Yeah, so first I would say I can't think of a single program where you have an ability to develop an oral drug that can mimic biologically and hopefully clinically the effect of an upstream monoclonal antibody. I don't believe that there has been a case of a target that is so well positioned to create value for patients and obviously for Kymera in the space in the past 20, 30 years. And the beauty is that STAT6 is the selective transcription factor for the IL-4 receptor alpha, which means that when IL-4 receptor alpha is activated, actually STAT6 is recruited to the receptor, is phosphorylated, and goes into the nucleus. There is a very linear relationship between the two, which means that if we can block STAT6 and degrade STAT6, we should be able to have a dupilumab-like effect.
That's really the premise and the excitement around the program. There is about 150 million patients suffering from TH2 inflammation, and a small fraction of those patients are served by existing biologics. What we want to do at Kymera is not so much just to have an oral molecule that has biologics-like activity, but actually our ambition is to change how patients are treated. If you're able to develop a drug that can be given orally to every patient without the complexity of an injectable biologics, you should be able to bring this drug at the forefront of treatment paradigm across a series of indications that TH2 inflammation is relevant in, going from AD, atopic derm, to asthma, to COPD, to chronic rhinosinusitis, to EOE. So the opportunity is vast.
What we've shown preclinically in both cell systems and preclinical studies is first that this is one of the few ever characterized small molecule drugs that is actually more potent than an upstream biologic. So we're able to block the pathway in cells with pico- or nanomolar concentrations of KT-621. We've shown in preclinical studies, for example, in an asthma model that we presented at ATS a few weeks ago that we're able to impact downstream TH2 biomarkers equally or sometimes even more potently than dupilumab. And also we can have an impact on disease as we've seen in the lungs of this lineage of these mice. We've also shown that with oral low doses, we're able to degrade the target in a dose-responsive manner and completely at the higher doses in the 3-10 mg/kg basis in non-human primates or dogs, we're able to completely deplete STAT6.
We've also run extensive preclinical safety studies, and we haven't seen any adverse events in those studies, even at very high concentrations. With regards to where we are with the program, we've been saying from the beginning of the year that we are in IND enabling studies, and we haven't updated on what's going on in the IND enabling studies. We have a custom of just disclosing when the IND has been cleared. They're actually more likely when we dose our first subject in phase one. And I think at that time we can also look back and talk qualitatively about the IND campaign.
KT-294, your TYK2 degrader, which is set to enter the clinic in the first half of 2025. Can we talk about this drug's profile versus approved deuterated TYK2 inhibitor deucravacitinib or other TYK2 inhibitors in development, including from Takeda or other private companies like Alumis or Sudo Biosciences?
Sure. So TYK2 is another amazing target if we think about human genetics and what companies have been able to do. And obviously, lots of credit goes to BMS for being the first company to bring a molecule that validated the human genetics data. So it's a beautiful story of genetics and drug development. So I actually mentioned genetics twice. I'm going to mention one more time. I think if you look at human genetics, you'll see that there are subjects that have a complete loss of function of TYK2 that have a very unique phenotype. They basically have non-functioning IL-23, IL-12, and type I interferon. If you look at the kind, it's that genetics, those subjects only have one of those three pathways, which is only the IL-23.
So the opportunity we have with a degrader of TYK2 is our TPP is really to deplete TYK2 from the immune system of our patients. And we believe that if we do that, we should be able to have a biologics-like effect. So our goal, to be honest, is not just to bring another TYK2 agent to the clinic or eventually to the market. I don't believe personally that we need another TYK2 agent. Our goal is to bring a TYK2 degrader that will have a biologics-like, a Stelara-like activity. If we're not able to show that in clinical development, we have no interest in actually spending time and resources for a marginal improvement over the existing growing landscape.
No, makes complete sense. Shifting a little bit more to your oncology assets, KT-333, your STAT3 degrader. Where will you present data in a poster for your STAT3 degrader, KT-333, at EHA this week? Can you characterize the clinical data that you've shown so far and what we should expect at the EHA conference versus what was in the abstract?
Yeah, so this is another program where what's transpiring in the clinical investigation is exactly what we've seen preclinically. This is one of the things that personally I'm most proud of at Kymera. Every program that we've taken in the clinic, and it's been four so far, soon to be five, there has been high fidelity of translation between what we've seen preclinically and what we see clinically, which obviously should bode well for the immunology program we just talked about. Obviously, if we translate what we've seen preclinically, these are going to be huge drugs. So going back to STAT3, what we've seen preclinically, really robust activity in some heme subsets, especially T-cell lymphoma leukemias. And what we've seen preclinically is that in solid tumor, it really requires a combination approach.
So then what we've seen now in the clinic, we've seen robust responses in CTCL, and we've seen a very exciting emerging signal in Hodgkin's lymphoma. As of the abstract, we saw 2 out of 2 complete responses. Both patients actually ended up going to potentially curative stem cell transplant. So we are definitely, and these are both patients that have gone through first line with Adcetris, ADC, second line PD1, refractory to both, come on STAT3 degrader, and complete response. So this is a drug that has the potential to change treatment paradigm in that particular subset. And so this is an area that we'll be focusing probably at EHOD. I won't go into the numbers.
What I will say is that we expect by the end of the year to give an update that will be comprehensive of escalation as well as, let's call it, last cohort, small expansion before we go into phase 1B studies. And I think, again, having an exceptionally well-tolerated drug in oncology where the most common adverse event is mucositis grade 1, 2, so relatively benign, really bodes well for the opportunities that this drug will have in these potentially heme opportunities as well as combo in solid tumors if we end up exploring that clinically.
Looking broader to the competitive landscape, can you talk about the challenges the field has faced when targeting STAT3 transcription factor, and why you believe degradation presents an advantage?
Sorry, just drinking here for people online. The STAT3, it's a great question. STAT3 is a transcription factor. STAT3 is difficult to inhibit, and also a non-SH2 domain activity. We believe that it's critical to remove STAT3 to evaluate and ask the question of the full clinical activity of STAT3. Generally, it's been difficult to inhibit because it doesn't really have a catalytic site. We also believe that in order to maximize the biology of the target, you have to degrade it. That's why we built this program. I would say that for every agent that we've seen targeting STAT3 in the past, I believe we have the most specific and also cell-type agnostic degrader. We had a great presentation. I encourage everybody to check it out.
AACR actually on STAT3 that talked about why we ended up choosing VHL as the E3 ligase for STAT3 versus other E3 ligases. That was driven purely by biology. We wanted to make sure that we had maximal degradation across all the type of tumor that we were interested in. We saw that there was a discrepancy with Cereblon, but there was high fidelity with VHL. So it just speaks to the amount of work that has gone into building a degrader for STAT3. We're excited about what we've shown so far and helping patients actually live longer.
Saving the best for last, MDM2 degrader, KT-253. You recently presented initial proof of concept data at ASCO for this asset. Can you give us key takes from dose escalation data where you saw clinical activity, including two partial responses and one complete response at dose levels one and two, respectively?
Yeah. So again, I don't want to repeat myself. This is another program that when we talked to our stakeholders in the past two years, and our thesis was if you degrade MDM2, at least we had shown it preclinically, and you dose infrequently, you'll be able to maximize anti-tumor effect in highly sensitive tumor types, and you're able to mostly overcome the dose-limiting toxicities that have plagued the MDM2 space, namely thrombocytopenia, neutropenia, in many cases, diarrhea. And so our point has always been, we believe that by degrading MDM2, we commit tumor cells to an apoptotic response. We've shown it with data, tumor cells to an apoptotic response. This apoptotic response will not be present in healthy cells. Small molecules cannot do that because with the degrader, we overcome the feedback loop, and that's the therapeutic index.
And I think the most satisfying thing is when these theses play out in the clinic. And I think the main take home for me at ASCO was actually this, was the fact that we were able to show anti-tumor responses, as you mentioned, in a few patients, even at the early doses, in the complete absence of the typical neutropenia, thrombocytopenia. That has never been shown in the MDM2 space. I believe that this is still underappreciated for that program, and hopefully there will be more attention to that program going forward. And I think what's ahead of us for that program is, okay, now that we've shown something that, to be honest, probably few believed was possible, where are we going to develop this drug in? So it's clear that we have an early exciting signal in AML. So AML is a clear opportunity.
We've shown preclinically, actually, even in combination with venetoclax, we see some amazing activity. So there is a clear path, both the single agent and combo in AML. And then in solid tumors, where the question is, which tumor types are these highly sensitive where you can create this therapeutic index of activity in the absence of dose-limiting toxicity? And so we will give an update in the second half of the year on the work that we've done in terms of selecting the right patients for solid tumors. And that will be then followed by a clinical trial update still later in the year.
Perfect. Thank you. Zooming out a little bit more to the strategy and overall business development aspects of Kymera, what are your current partnering plans for your non-partnered assets in INI, STAT6, TYK2, etc.? Any color here?
No partnering plans. Easy.
Short and sweet.
Yes.
For particularly oncology, where you've shown initial clinical data and partnerships are key to perhaps further developments, how do you think about priorities moving forward in terms of investment between your many programs?
Yeah. I mean, what I said, I meant, maybe I'll add a bit more color on the immunology. So we believe we have a very unique view on target selection in protein degradation. If I had to say something, I believe our targets have been some of the probably more sophisticatedly chosen targets in the space. And I think it's nice to see there are other companies, large companies that followed us. If you look at other programs against IRAK4, you looked at other programs against STAT6, there are other companies who are clearly following what we've been doing in the space. And I think when you, especially when you identify these unique opportunities of matching the power of the technology with the biology and the potential clinical impact of the target, this is how big companies are built.
Given that we hope and plan to be a global commercial stage biopharma company, we believe these are programs that will enable us to grow into that type of company. It's also true that it's difficult to, given that we have an exceptionally productive discovery engine, and you'll hear more about our new programs probably next year, it's going to be difficult for us to execute all the way through in each one of our assets. I will say that for now, immunology is something that we're not even considering partnering. We want to create value, and in some cases, we might never partner if I had my choice.
I think there are other areas where it would be synergistic, whether there is a company that has a combo agent for maybe one of our oncology assets, where you see like you're really creating synergistic relationships, or whether it's an area where there is a synergy with a commercial footprint in that area that can maximize value and make NPV much more positive. Those are things that we would be exploring, again. But from the point of view of what's best for the company, what's best for patients.
You are well capitalized with $745 million, approximately.
That's what I heard, yes.
Last time I checked.
Yeah.
With runway into the first half of 2027, what does that runway entail? How can we think about bringing new candidates into your pipeline, including potentially a molecular glue asset?
Yeah. So we're very well capitalized. All the programs and plans that we've talked about on our pipeline are funded through the time horizons that we discussed. We'll have so many inflection points between now and then that it'd be even difficult for me to call them out individually, but obviously phase 1, phase 2s, and beyond for many of our programs. And including in that, there is also supporting the emerging clinical pipeline. So I think probably by this time, next year, we're probably talking about a new transcription factor degrader that we're building at Kymera in immunology. This is another program we're very excited about. We have molecular glue efforts within the company. Actually, there is a quite substantial effort in the space. And the reason is very simple. I don't divide molecular glues and degraders by different properties.
I think if you've been in this space long enough and you know what you're doing, you should be able to make heterobifunctional degraders as well-behaved oral molecules. For me, it's more about what is the technology need, what is the target need, what is the technology bringing to the table. So we've learned we're not the only ones that some targets are not ligandable in a specific binding event by small molecules. And so for those targets, we believe that protein-protein interaction-driven pharmacology as molecular glues is the answer to that question. And so that's where we're spending quite a bit of time. And hopefully, again, it might be that next year we'll talk about also molecular glue program.
I'm going to squeeze one last question in here. Any color for the balance of the year on what your capital allocation priorities will be?
Well, I think capital allocation is really our job, and it has to be based on the priorities of the companies and the probability of creating value. So I think it is, given that actually 474 is a program where we're not actually investing money, given that Sanofi is running the program, is spending the money. Actually we have milestones that have come in late last year. Clearly, advancing STAT6 and TYK2 into clinical development is a high priority. Continuing to support the oncology pipeline in the clinic to, again, build value there is another important priority. And then making sure that any program that we bring into the clinic has large clinical and commercial opportunities that make the investment thesis very simple. And we don't want to have to spend a lot of time making a decision on a program.
Usually, that means that there are too many questions on that program and not enough answers.
Well, on that note, thank you so much. My name is Karishma Raghuram here with the Goldman team. Welcome to Miami. Have a wonderful rest of your day, everyone. And yeah.
Now we just need the rain to stop.
I know. He would hope.
Thank you.
Thank you.