Welcome back to the 46th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here at TD Cowen. We're really happy to have with us Nello and Jared from Kymera, CEO and CMO to talk about a variety of programs. We'll probably spend a lot of time on STAT6, but we will definitely get to some other programs as well. Maybe to start off with, Nello, you wanna kind of give a high level kind of status update of the company maybe, and what you view as kind of the key value-creating milestones for shareholders over the next 12-24 months or so?
Yeah. First, thanks for inviting us. Thank you for running this conference in Boston, so we can stay home. Let's talk about Kymera, and I think what we've done and what we're trying to do. I think, you know, in the past few years we've demonstrated that if you select the right target in highly validated pathways that have, you know, injectable solutions, injectable biologics as a treatment solution, you can potentially change how people can be treated with these diseases. Obviously, we're still far from, relatively far from commercializing our drugs, but we've shown both pre-clinically and clinically that you can develop really unique and potentially transformative profiles.
We focused on pathways that have millions of patients that are served by existing solutions with the hope and the ambition to actually expand their market access to many more patients, we like to think many more millions of patients. STAT6 is a great example of what one can do if you select the right target and the right pathway. IRF5 I think is another amazing example of a genetically validated target in pharmacological and clinically validated pathways that has a really unique profile. We have several other programs that are just as exciting that we know we're very eager to be in the position to sharing more about them, hopefully in the near future. What's, what's ahead of us?
I think for what was really critical for Kymera in the past few months was initiating the first 2, for Kymera, the first 2 global phase 2B studies, where we're evaluating KT-621 in 3 doses plus 1 placebo across atopic dermatitis and asthma, both diseases that don't have a safe and effective oral option today on the market. The team has been extremely focused on making sure we have the right protocol, the right sites, the right patients on the study, and so they're doing a great job. We're enrolling at a pace that we believe keep us at least on track based on what we've shared externally in terms of timeline. It's gonna be extremely exciting to have 2 big datasets next year by middle of the year AD, by end of the year asthma.
We'll have roughly 500 patients worth of data across these two Type 2 diseases that we just talked about. Those are, let's say, the more longer-term milestones. This year, in the next really few months, we've initiated the phase 1 healthy volunteer study for KT-579. Again, another first-in-class degrader in for, in this case, IRF5, a key node in inflammation that has strong genetic association with lupus, IBD, and RA. We started the study a few days ago, you know, week or so ago, we expect to have the data, the phase 1 data, in the second half of the year. As we've done with KT-621, we'll share the totality of the data.
We're not planning to share any data between now and when we've completed the study. We expect to be able to start a patient proof of concept study soon thereafter. I don't wanna say exactly when until we get a bit deeper into the healthy volunteer study. This year, again, phase 1 healthy volunteer from a potentially impactful, really potentially largely impactful program, another first in class program. We have a couple of important, I would say, corporate, and also R&D milestone. One is, with our partner Sanofi, we plan to initiate a first phase 1 study for the second generation IRAK4 degrader. This is for KT-485, this will be our third clinical program, which will also bring in a milestone.
And then with with our partner Gilead, we hope to being able to hand off to them our CDK2 degrader, molecular glue degrader, which has a very unique profile. We haven't been able to really disclose much about their program, and hopefully at some point we'll be able to do so. This speaks again to the capabilities that we've built to go after these extremely difficult to drug target with the fit for purpose technology. They're bifunctional degraders, molecular glues, and you'll hear more about even other modalities as we continue to expand the company.
Okay. Maybe we'll start, it could be for either of you, just with the phase 1 data that has been released for KT-621, STAT6, what do you think, you know, it was a fairly extensive phase 1 program between the healthy volunteers and the AD patients. Just what are the major questions about KT-621 that you think are now resolved and kinda what is that big question still remaining for you to figure out with KT-621?
Yeah. You know, last year, we had put on that KT-621 roughly 200 humans between healthy volunteers and patients. It was actually a pretty broad phase 1 campaign. Maybe going back to the promise of STAT6. As you know, targeting IL-4 and IL-13 is the most validated mechanism in Type 2 diseases. When I talk about Type 2 diseases driven by, you know, again, Type 2 inflammation, which are AD, asthma, COPD, eosinophilic COPD, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria, EOE, and probably two or three more that I don't have to spell out. These are again. Probably more than 100 million patients diagnosed with these diseases. Dupilumab has been though.
Actually, I would say all drugs in Type 2 inflammation, there's been about 2 million people, patients put on those drugs, whether it's dupilumab, even JAK inhibitors. We have a huge unmet need here of having moderate... even just moderate to severe patients, which is about 50 million patients, have access to advanced systemic therapy. Why does STAT6 come in? Because it's the obligate transcription factor of IL-4 and IL-13 signaling. We have shown preclinically that if you block STAT6 from signaling through degradation, we can block IL-4 and IL-13 just as well as dupilumab. The question in the early development was, do we block? Can we degrade STAT6 robustly and in all relevant tissues?
Does the STAT6 degradation lead to a similar downstream effect as IL-4 receptor alpha, which is the target right upstream of STAT6, which is the target of dupilumab. I think we've shown very conclusively that we can degrade STAT6 completely, basically, in both healthy volunteers and patients. That leads to downstream effect on all Type 2 biomarkers that you can imagine, at least as well as upstream biologics, and actually in some cases even better if you look at Eotaxin, if you look at FeNO, if you look at IL-31. What does that mean for patients that have Type 2 diseases? We had patients with AD, we had patient with comorbid asthma, comorbid allergic rhinitis, and all the clinical endpoints were positively impacted by STAT6. Going back to your question, what did we answer?
We answered that STAT6 degradation can phenocopy IL-4 receptor alpha blockade. It can do it safely, and that leads to an effect that is very robust and at least comparable to upstream biologic. What's left to do? I think what's left for us to do are two important things. One, continue to demonstrate that the safety is in line with our expectations. Second, fully evaluate the clinical activity of our drug. So far, 28 days, we really don't know where the maximal activity of our drug in AD, in asthma, and other diseases. In these phase 2b studies, we believe we'll have a close to complete de-risking of the program given that we'll have 16-week data for AD, 12-week data on asthma. We'll have 52-week OLE in the AD study.
I think we'll get a full sense of what STAT6 degradation can do for patients.
Maybe Jared, just one of the things that obviously as we get some of that longer term data is what's the long-term outcome and compare that to a, to a dupilumab, you know, which the comps are pretty straightforward. You know, the other thing that can impact treatment decision is kind of the time to efficacy for patients, particularly if there's, you know, more acute symptoms, particularly in AD. How do you think the onset of action compares to 'Cause maybe that we already know a little bit more about with 28 data.
No, I mean, I think we were very encouraged by what we saw in phase 1b in terms of onset of action. You know, first of all, the degradation itself happens very quickly. You know, with multi-dosing within 4 to 8 hours of the first dose, you've essentially maximized degradation of the target. It remains down as long as you're continuing to dose. We know the pharmacological effect is rapid, and that then translates into a rapid effect, not just on circulating Type 2 biomarkers, but a rapid effect on improving EASI scores, on improving pruritus. You know, we saw this, you know, as early as within the first week of treatment, with the 28-day treatment.
In fact, what you saw, which was very encouraging, is that not only does it happen early, but you continue to see improvement even through day 28. There's no plateauing of the response with regard to EASI or Pruritus, for example. It's quite possible, and our expectation is that if we dose beyond 28 days, which is what we're doing in the phase 2B studies, we should see continued improvement. If we look at it and compare it to dupilumab, and it's always a little bit tricky comparing across studies. In general, if you look at what dupilumab saw in their studies at 4 weeks, it's very comparable in terms of the impact that we're seeing on Pruritus, on EASI. You know, pharmacology with antibodies like Dupixent, also the onset is fairly rapid.
I think we'll have a better sense for how we compare in terms of kinetics when we look at our phase IIb data, which is now looking at the traditional 16-week endpoint in AD, and then of course, going even beyond that to 52 weeks in the open-label extension study. I think that'll give us a better sense. I think we're also very encouraged by safety, which is different from the question you're asking, which is on the kinetics of response. What we are seeing are rapid kinetics of response, that I think bode well for being able to hopefully phenocopy or at least phenocopy the clinical activity of Dupixent.
Okay. And I Within the phase one data, there was also the comorbid asthma patients in there, where you're able to show FeNO reductions. What do we know about patients that have comorbid asthma and AD?
Mm-hmm.
You know, are those patients maybe hypersensitive to IL-4 13 'cause it? I mean, they have two different potentially TH2 driven diseases that's really selecting for who clearly has TH2 driven disease. Should we think of them as acting kind of just the same as a general asthma or a general atopic dermatitis patient?
Well, I think in general, patients who have multiple Type 2 diseases are more Type 2 skewed, right? They're more likely to have their diseases that are even more
Dependent on IL-4, IL-13 signaling, you tend to see higher levels of typical Type II biomarkers in the blood. That's, that's not unusual in people. It's not uncommon for patients with AD to have comorbid asthma. I think you see that in about 20% of patients with AD. Allergic rhinitis, comorbid allergic rhinitis in about 40% of patients with AD. It really isn't uncommon at all, and having those patients on our study just gave us a really nice opportunity to show activity, you know, in those diseases over a 4-week period in addition to what we saw in AD.
Sorry, can I add something? We don't have a timer, you're keeping track.
Yeah. Okay.
Okay.
Yeah, we're just gonna go all day.
No, because I always I titrate my the answers.
Yeah
... based on time, so I'll keep going. No, the point that you made actually is a very good one though, that if you have comorbidities, it's very likely that a lot of your disease is the Type II skewed even beyond just what we know about AD. I think the beauty about dupilumab, which is the most successful drug into all these diseases, is the fact that it treats all comorbidities. Unlike many others actually that are, they're either being investigated or, been approved in the space, the reasons why a lot of prescribers prefer dupilumab is because it's extremely rare to have a Type II disease only and to have only one. If you can treat one and their comorbidities, you'll have. You know, obviously, the patients will be happier.
Okay. obviously, I know very much the goal is just phenocopy Dupixent, but pre-clinically in several models, you did have kind of trends actually in KT-621's favor of somewhat better efficacy. You know, there's certainly ways to interpret some of the biomarker data and FeNO data to suggest that maybe you're also seeing a bit better response. You know, When we get that phase II data, what would convince you to be a little bit more?
Yeah
...aggressive that there's an efficacy argument here?
No, just to be clear, you know, just not to correct you, but I will. It's not that our goal is to phenocopy Dupixent. I think what we've seen, in all of our preclinical studies and the way that the biology can be evaluated is that given that STAT6 is right downstream of the receptor, in fact, it is recruited to the receptor upon receptor activation, our base case expectation has always been, okay, if we block STAT6, we should see the same effect as dupilumab. It's not even our target product profile. This is just an observation, and this is why we always have said that we expect it to be at least as good as these upstream biologics because that's what the biology has told us.
We are very eager and curious about what is the clinical activity with STAT6 degrader. Our benchmark is always been these upstream biologics because it makes sense that if you block right downstream, you would have similar activity. For us, this is about an oral drug that is highly active, that is hopefully highly active, that is hopefully very safe and tolerated, that can change how doctors prescribe drugs to these patients. In a way, whether it's exactly like dupilumab, slightly better, slightly worse, won't even matter at that point. The goal of this phase II study is we have two goals. One is if it's run successfully, we get to select the dose for phase III, and we can go into phase III.
The other goal, and I'm not saying one is more important than the other, the other goal is, okay, to fully evaluate what is the clinical activity and the safety associated with it of STAT6 degradation.
Okay. We do have a timer now for you.
Oh, now. Okay.
you can appropriately titrate.
Yeah.
The so we obviously had your dataset. There's over the last handful of months, there's been several kind of early mid-stage datasets across atopic dermatitis with different targets, some more novel than others. Just what's your view, kind of roll the clock forward, how do these fit together? What does the treatment paradigm-
Yeah
for AD look like in a few years with all these targets coming up?
Yes, I will start with the kinda the same answer as before. We need more therapy. This is not a zero-sum game, this is really advancing multiple therapies in these huge disease populations. If you look at psoriasis in the past 10 years, the market has grown 5x, I believe, thanks mostly to additional therapies. There are multiple multi-billion dollar drugs in the psoriasis space, clearly, we need more active drugs. I think some of the mechanisms that are out there will get to the finish line. Some won't. I'm not gonna get into what I believe will make it or not. I think we do need more therapies.
I think the beauty about a drug like STAT6 and KT-621 that is a drug that is providing, again, an option for patients with this TH2-driven inflammation, in a pathway that has been validated by drugs being in a billion, millions of patients at this point, as I said, a couple of millions, ages from infant all the way to adults. It's about providing a much needed, convenient, effective, and oral therapy. I suspect, and our goal is that our drug, KT-621, will be the first line drug for all patients with Type II diseases. That is what our goal is, and I'm sure there is option, many other options that will come after that with all these other mechanisms.
Okay. Here's a little bit more of a Jared question. Just on the dose selection, so obviously you're doing a little bit more dose ranging with the phase and much more robustly with the phase twos that are ongoing. Do you expect to be able to select a single dose in a phase three? You know, we often see still even with phase two dose ranging, you know, two doses advanced in I&I indications into phase three. Just how should we think about the ability of how robust of a dose selection you're gonna be able to make on these phase twos?
You know, Marc, I think our expectation is that just given the huge sort of PK/PD data set that we had from our phase 1 campaign, right? In both healthies and patients, we learned a lot about the drug and its behavior. That allowed us to really be very sort of confident and strategic in how we pick the doses for phase 2B, the 3 doses. We actually have the same 3 doses in the phase 2B asthma as well as in the AD study. I think both of these should give us a very high probability of success of coming out of those studies with a single dose for phase 3. Now, whether it's the same dose coming out of the phase 2B asthma study for phase 3 that...
comes out of the AD study, we think it's likely, but that's not certain, so it remains to be seen. I think a successful phase 2B for both of these indications would be that we're able to come out with a single phase 3 dose that we're confident in and can then move forward with.
Okay. In one of the safety events that we do see with this broader pathway, the IL-4 13's, particularly in AD, is a conjunctivitis, which you have not seen yet. Is your expectation with longer follow-up, you will and larger numbers, you're going to start to see it, or are you starting to get with the number of patients you have on drug, a little more confident that maybe that is a small difference between STAT6 and IL-4 targeting?
I don't know what you're asking in the second part, but, with the phase 1B-
Yeah
we'll, we'd kind of do the analysis from there. I don't believe personally that we have enough patients or on a long enough duration of treatment to being able to credibly answer the question, do we have conjunctivitis or not? I think it's just I think what we could say, though, that, you know, if we, if you kind of do the math, 28 days, dupilumab incidence of conjunctivitis is about 5%, so about 1 and a half patient in our study should have had conjunctivitis. If we haven't seen it probably means that it's not worse, but I'm not sure we can say credibly that it's less or no. I think the goal of this study, again, of the ongoing study, is that I think we'll learn about that as well.
Okay. Then maybe when we think about AD versus asthma, you know, is there a difference in kind of what the value proposition of moving to an oral therapy looks like, considering, you know, in AD that this may be the only drug they're taking versus asthma that's a little less likely, right? They're taking.
Well-
...a lot of other things.
Yeah. I actually believe that, I think this is a paradigm-shifting type of therapy that is much... I would argue it's just as needed in asthma because if you look at the treatment paradigm in asthma, we know we spent, like, 2 hours yesterday to actually talk about this at Kymera. If you look at the treatment paradigm in asthma, patients that become eligible to advanced systemic therapies like dupilumab and others, have gone through years of taking controllers that actually, you know, inhalers mostly, that don't really address the underlying inflammation. I actually think that is completely wrong from an ethical perspective to put children and adults on multiple year of therapies that don't address the underlying inflammation.
I think the opportunity we have with a drug that hopefully works and is safe and is oral and should be easily accessible from a patient perspective, that we can change that. We're gonna have people on KT-621 when you have eosinophilic asthma. That's it. That's the ambition. Obviously, it's complicated to get there. We might have to do it stepwise. That's really... If you're in the biotech industry and you wanna innovate, you have to commit to innovation all the way, not just in R&D.
Okay. Maybe one other way the I&I space is innovating is there seems to be an increasing push across a variety of I&I diseases on combination therapies or bispecifics. You know, obviously, this is one pathway. One, do you believe that that's a trend in these specific diseases that is gonna happen? Two, if so, when's the right time to start thinking about combining KT-621 with some other mechanisms.
I mean, I think immunology is just a bit behind other diseases like oncology, where, you know that combination allows you to have deeper and sometimes broader or sometimes both, results or impact on diseases. I think it's only natural that we will go into combination. Often, I think we're learning. Somebody told me in a big pharma company, "Nello, you know, this bispecific one plus one sometimes is three. In most cases, it's minus one." We have to really learn how the biology works and also the geometry and the kinetics and the kind of cell-cell interactions of these mechanisms are gonna play out.
Again, not because I'm biased, but I think the flexibility of combining two oral mechanisms, I think is much more rational than combining biologics in a bispecific fashion. Obviously, we're a bit behind given that for biologics, it's an engineering question, much more so than a scientific question. I think the future will move into combination. The short answer is we're doing a ton of work pre-clinically to both understand what are the right combination partner and to build programs to continue to be innovators.
Is that a?
A relatively near-term thing that may happen, that you put some more molecules in, that is the goal? Or is that just a very long-term vision?
Well, I mean, you know, there is no long, you know, there is not. You know, we're talking about biotech years, not. It will, it will, you will hear things from us about this concept in the relatively short to midterm.
Okay. Okay. Maybe we'll move to IRF5. maybe just I think it's a target a lot of people are not super familiar with. It Despite I know you did an R&D day that had a big focus on it about a year ago. you know, wanna remind people just kinda why is this an interesting target and kind of where does it where does it make the most sense from a biologic perspective?
Maybe I'll answer the first one, Jared can speak to you about, you know, what's the right application of it. IRAK4 is one of the few targets that has been the Holy Grail of immunology, and it's been one of the most technically challenging targets in the biopharma industry. Why has it been the Holy Grail and why has it been the most challenging target? The Holy Grail is because there are very few mechanisms that have strong genetics association with diseases, and the human genetics of IRAK4 with especially SLE, and I would argue IBD, is one of the strongest out there. It's not surprising that every company that is working in immunology that has a credible R&D organization has been working on IRAK4. Now why has it been challenging is because there are multiple IRFs.
I think there is 12 or 13 or 11. I should know this, right? I always say 10, 11. I should get the answer from the team. Within this category, right, you need to target only IRF5. Then IRF5 has multiple, you can call it splicing variants that you want to address all of them. The beauty about protein degrader, you can have a binder that is neutral to the function of the protein, and you can select the site that is not in all the other IRF, but is conserved in all the other IRF5 splicing variants. That, I would say from a technical perspective, me as a chemist by training, as being one of the most complicated endeavor at Kymera.
That's why I think you've really only seen us having a real program that is now in the clinic. I think the opportunities are huge, but Jared maybe can speak to them better.
I mean, you know, I mean, IRF5 controls 3 primary pathways that drive diseases like lupus and RA and IBD. It controls Type I interferons, it controls pro-inflammatory cytokines, and it controls B cell activation and autoantibody production. There's clinical validation that drugs targeting 1 of those pathways, you know, SAPHNELO for Type I interferon, BENLYSTA for B cell activation in lupus, for example, there's clinical proof of concept going after 1 of those 3 pathways. Here we have an opportunity to actually hit all 3 of those pathways to treat diseases like lupus, Sjögren's, and IBD. That's really the value proposition here is to be able to do that. There's the genetic validation, but there's also the clinical validation for the individual pathways, and now the opportunity for a drug that hits all 3 pathways.
I mean, lupus is certainly high up on our list because for the reasons Nello gave, because of the genetic validation, this clinical validation I just spoke of and our very strong preclinical data across multiple animal models of lupus. Right now we're in a phase I healthy volunteer study that we just started. We plan on reporting data out, you know, the second half of this year.
Sort of on the heels of that, we don't know exactly what the timing of that, of that's gonna be, but it's highly likely that lupus will be the first indication that we move into to show the first proof of concept in patients for, you know, the obvious reasons about that's where the genetic and clinical validation is, that's where the preclinical models show the most strength, and there's a very high unmet need there obviously.
Okay. What will we be able to learn from the healthy volunteer portion before we get to that potentially lupus or the other one?
The healthy volunteer, you've seen our phase 1 studies before, so you know we have single ascending dose, multiple ascending dose studies. Certainly, we wanna be able to learn within that study, you know, are we able to achieve at least greater than our 90%, you know, IRF5 degradation in blood at doses that are safe and well-tolerated. That's always what the number 1 objective. I think we also have an opportunity, not the same opportunity as STAT6, where there are circulating biomarkers, inflammatory biomarkers in healthies that you can follow, those same sorts of biomarkers. Circulating biomarkers don't exist in normal individuals because IRF5 is not normally activated in healthy individuals 'cause its expression is restricted and its activation is very context specific.
Here we rely in phase I on ex vivo stimulation, so taking blood out and stimulating across multiple different TLR pathways, where IRF5 is very important in signaling through those pathways that are then leading to activation of these three pathways I just talked about before, Type I interferons, pro-inflammatory cytokines, and B cell activation. We'll have an opportunity to look at those, the activation of those Toll-like receptors in vitro, TLR7, 8, and 9, and look at biomarkers downstream of that. That will give us a good sense. We'd like to see that robust degradation of IRF5 in the blood is associated with substantial inhibition of all three of those pathways as evaluated through these ex vivo stimulation assays.
Uh-
Can I just add? I know we're out of time.
Yeah. Big picture.
A quick thing. The question is why is IRF5 activation so prevalent in these diseases? What we were able to learn preclinically is because it activates these three pathways. If in healthy volunteers we can show that we block these three pathways, it should tell everybody that there is a high probability that it will work in these diseases where there is genetic association. I think it comes full circle just after even the healthy volunteer data. Okay. As I said, unfortunately, we're out of time, so we're gonna have to cut it off there, but thanks a lot, Nello and Jared for joining us, as well as everybody in the room and on the webcast.
Thank you.
Thank you, Marc.