Back to school conference. We're thrilled today to have Kymera Therapeutics. We have CEO Nello Mainolfi, and we have Bruce Jacobs, CFO. Guys, welcome. Good to see you.
Hi, Geoff. Thanks for having us.
Back to school.
Yes, exactly. For those that may not be as familiar with the story, just give us the two minute. I know you're long-winded, so we'll try to keep the buzzer there.
Okay, good.
Starting good with Geoff. All right. The long story is we started Kymera 10 years ago, so I am going to go year by year now.
Yeah.
The idea was high level, really simple. There is tons of targets that have not been drugged. There is tons of genetics information we have, but we have lacked the technology to go after these targets effectively, selectively, and potently. We thought that targeted protein degradation, which is a small molecule modality that can remove disease-causing protein, was going to be that unlocking technology. We spent the past 10 years, we put actually, I think by now, seven molecules in the clinic. We have shown that you can degrade, specifically, potently, selectively, and with patient impact, proteins that have historically been undrugged. In the past, let us say five, six years, we have decided to focus almost completely in immunology for a couple of simple reasons.
One of the biggest markets, dominated by biologics, with tons of opportunities to change the treatment paradigm and impact millions of people around the world. We have developed, I think, one of the most exciting immunology pipeline in industry with STAT6, which is obviously downstream of IL-4 receptor alpha, and we believe one of the most exciting drugs, if not the most exciting drug, for type two inflammation, which is tens of millions of patients. We have an IRF5 program, which is targeting this incredible axis where several pathways signal through a B-cell, type I interferon and downstream, and other inflammatory cytokines. We have other programs that we have not disclosed, and we have partnership with Sanofi and Gilead. This is a big year. We have big readouts for both IRF5 and for STAT6, so I will pause here.
Yeah.
We can go from there.
Well, let's talk about the data for STAT6 by the end of the year. Help frame how you think about this. Obviously, most people are thinking about this from a Dupixent context or from other standards of care. But at this point, does oral convenience sort of outweigh the. Obviously, you want efficacy, right? But does the oral anchor the differentiation piece, or maybe help us with the profile?
Yeah. So, great question. Taking a step back, there are nine indications in which Dupixent has been approved. If you look at worldwide, we're talking about more than 100 million patients. When you think about STAT6 and KT-621, we need to remember, this is one of the few mechanisms, the other one is IL-4 receptor alpha, which is Dupixent, that have potential to address several comorbidities of patients with type two inflammations. Many patients, even north of 50% in some cases, have comorbidities. I would start there, just an important description of the opportunity. Then if we just take one of those indications, and let's say AD, atopic dermatitis.
If we do the math, in the U.S., there is about, depending on the literature you use, between 6.5 and 9.5 million patients with moderate to severe AD, 12 and up. Let's use 7 million as the number. There's only been about 400,000 patients that have been dosed with an advanced systemic therapy, and this is DUPIXENT, RINVOQ, and others. So roughly about 5% penetration in the moderate to severe atopic dermatitis patients. Why such a small penetration? Because most patients, and this is work that we've done, so this is not me speaking, this is market analysis that we've done. I'm still speaking, but it's coming from others. Why such a small penetration?
Because most patients and most prescribers feel that, "I'm not severe enough to be on an injectable biologic or on a drug that has black box warning." What are they looking for? Safe, effective oral drug. It actually goes, Geoff, exactly to your question. Safe, effective oral will transform this space. It's not about dupilumab or not. It's about safety, efficacy, and we have millions of patients that are untreated or poorly treated with messy topical. This has the potential to be the first in line drug for millions of patients that right now are undertreated or untreated. If you look at, sorry, other comps, I'll actually get to your question eventually. If you look at other comps in the space, look at psoriasis, SOTYKTU, great launch. Psoriasis, much more mature market, still one of the best launches in the space. Why?
Because it's a safe and effective oral. Not because it's actually the same efficacy of biologic. It hasn't. If you ask me, though, scientifically where do you expect KT-621 to land in terms of impact on signs and symptoms of AD? I will say that will likely be in the dupilumab ballpark, because that's what we've shown for the past five years. But I will say we don't need to have a successful drug.
Right. Yeah, and let me just follow up on that. If you think about getting into maybe healthier, slightly less severe patients, what would you anticipate maybe a duration of therapy for safe, effective oral to be? Would it be 2x, 3x what we see with dupi? The second part of that is that are there lessons to be learned for the patients that maybe dupi stops working, or is it tolerability or whatever, that you have a stoppage of therapy that mechanistically maybe use TPD, use the mechanism a little bit more broadly?
Yeah. That's a lot in there. Let me start with the second one. We know that people stop injecting themselves with DUPIXENT. That's a fact. I think that happens sometimes because you lose insurance coverage, and we've seen patients on our study that come onto our study because the insurance doesn't cover DUPIXENT anymore. People stop DUPIXENT because they don't want to inject themselves anymore. Then I think some people, although I actually don't know the exact number, might lose the level of efficacy that they were seeing early on. What we allow in our clinical trials are the patients that have stopped taking DUPIXENT, not because they have stopped responding, but for other reasons.
We have non-refractory patients on our study, and it's important to have them because we believe it gives us people also data to believe that they can stop those type of drug and come onto our drug. With regards to dupilumab refractory patients, I don't think it's well understood what the biology is. I believe there was a study that was run, I believe, by Eli Lilly with Ebglyss that showed that 50% of refractory patients with dupilumab showed activity with Ebglyss. There's clearly maybe some level of biology that is maybe irrespective of the pathway, and then there is some that is probably have to do with the pathway. But I wouldn't say that for a drug like ours, this is a first-line drug in the broader moderate to severe population. That's not really the problem we're trying to solve.
We're trying to expand access to many more patients that right now are not on biologics.
Right. Maybe talk about the BROADEN trial. How should investors compare the BroADen population versus prior dupilumab studies, in terms of baseline and prior treatment population, just to see what differences are this trial that could determine the results for BROADEN2?
Yeah. One thing to remember, if you look at dupilumab trials from 10 years ago or so, that was actually the first systemic drug, or the first targeted systemic drug, that was developed in atopic dermatitis. So obviously all naive patients with generally higher severity. In fact, the mean EASI at baseline in those studies were high 20s, early low 30s. If you look at atopic dermatitis studies in the past few years, you see the mean EASI at baseline, it's more often than not in the mid-20s. That's a natural evolution of the patient population. We go to all these clinical sites where patients have access to advanced systemic therapy, so the more severe patients are on advanced systemic therapies. These are still moderate to severe patients, they're just generally milder.
I think there is a school of thought that would say if you have less severe patients, actually, your probability of showing a reduction of EASI is lower because you start from a lower bar. I'm personally not a believer in that. I think that's an extremely weak argument. I think if you have a strong drug, it should work in severe patient and less severe patients. We've shown it in the phase I-B, although very small ends, regardless of the severity, we saw the same EASI reduction. With regards to others, to naive versus non-naive patients, as I just said, we allow biologics experience that were responders on our study. So obviously there is a population that was not studied back then in those days.
Otherwise, I think moderate to severe patients, we should be able to assess, in a robust manner, the safety and the activity of the drug. Again, I'm trying to stress that the focus should be less about how it compares to other drugs, but more on is it a safe and effective oral that can be the first in line, the post-topical drug in atopic dermatitis today? Because there are no drugs like this, even in development.
You mentioned safety. One of the safety issues with DUPIXENT is conjunctivitis. Maybe talk about high level, what kind of expectations you could have for this oral drug in terms of range of conjunctivitis you could expect, and what's the commercially viable option in terms of the rates you could get for conjunctivitis?
Yeah. I think historically what we've learned is that drugs that hit this pathway, whether they're actually IL-4 receptor alpha, which blocks IL-4 and 13, or IL-13 only Patients in atopic dermatitis studies and not in other indications. There is an imbalance between placebo and treatment in our conjunctivitis. I believe, this is my personal view, that these rates of conjunctivitis have been generally consistent across studies. While the numbers may appear different, I think just the way that now conjunctivitis is diagnosed in these studies is probably higher than it used to be back in the dupilumab studies, where it wasn't yet an AE of interest. I will just say that I've said this for years now. It's hard for me to know actually, even if I look at all these studies, whether there is a dose response, a concentration response to conjunctivitis.
It's not clear to me. I'm naively thinking that I think it's kind of all the same. Now, if you bring a new mechanism on the table, STAT6 degradation, same pathway, what do you expect? In the phase I-B, we did not see any cases. It was 22 patients for 28 days. Usually in 28 days, the rates are very low in the 4%, 5%, so it should have been one patient. Have we seen it, not seen it? It's not conclusive. Generally, I've said this again for a long time, I expect to see it because every drug in this pathway I've seen this imbalance, but we'll see. I think the data will tell us. With regards to the impact on different rates, I guess it depends on what they are. I haven't had conjunctivitis, so I can't speak for patients.
From what I've heard from dermatologists, it's not a reason for starting and stopping treatment of DUPIXENT, so I don't expect this to be a big dataset in terms of the impact of any potential conjunctivitis cases on adoption of these drugs. I guess we'll see, again, for STAT6 what we see, and then we'll go from there.
Now, give us the range of what you're thinking for phase III. As you look to the, at least the AD kind of study, is there potential for maybe an interim trigger on that just to call it early? Is it multiple doses? Do you feel comfortable in just using one? I know obviously it depends on the phase II.
Yeah. The phase II, obviously, one of the goals. So we had two equally important goals of this phase IIb study. One was to establish safety and efficacy in a global population in a placebo-controlled randomized manner, and at the same time, selecting a phase III dose. Ideally, I think it's not surprising if I say that ideally, we'd like to take one dose to phase III because it's easier, cheaper, and faster. But many drugs actually in these pathways have taken more than one dose in phase III, and Regeneron and Sanofi did the same because they wanted to make sure that they would select the right commercial dose. So we'll see. I think we're trying to figure out how we get this drug to market as quickly as possible. Again, assuming success in the phase II, because patients want this, a drug with this profile.
We're thinking about creative ways to get to market as quickly as possible. That includes how we design phase III, how do we get to the right safety database to enable an NDA, and obviously we have and we will continue to have regulatory interactions to ensure that we're holding hands in this process. It's too early for me to comment on specifics, but that's one of obviously the goal is to get to market as quickly as possible. Even if it's a month quicker, we'll do everything that we can to do so.
Yep. A topic term than asthma, obviously data-dependent. For the range of other indications, is there a path to run sort of a basket? Do you have to do a formal phase II? Can you go right to phase III? I'm just trying to think of ways
Yeah
To kind of there is tons of indications that you obviously
There are a ton of indication. In reality, four, five indications are 90% plus of
Yeah
The revenues of DUPIXENT. There is a component of impacting patients, creating values, and then there is a component of going as broadly as possible. If we think about four or five indications, our goal now that has to be vetted with regulatory agencies not to run any more phase II studies and go directly into phase III across these indications that we will disclose as we go into them. And we believe that the AD and asthma dose rangers will allow us to inform phase III dose selection beyond those two indications.
Maybe if you tie it to the mechanism, are some of these diseases more severe? In other words, would you need a higher dose for, say, PN or for EOE or something like that?
Yeah.
I'm trying to think of linking that to the STAT6 and the-
This is a dangerous question because this could be a long-winded answer, just so that you know. This is a great scientific question. First, what we learned from dupilumab is actually they have approved the same once every two-week dose in all indications besides EOE, where they're actually going every week, and the every two week actually did not work. You may be starting there. Why? I don't think it's ever been understood. Our hypothesis is that Dupixent is more sensitive to the local concentration of IL-4 and 13. We don't believe, and we have data to show, that our mechanism is not sensitive to local expression of IL-4 and 13. So we might not actually see those discrepancies across indications.
But what actually we will be able to see that other technologies cannot do is looking at systemic and, where possible, local degradation of STAT6, and then what that correlates in terms of efficacy. So those ranging studies would be critical to establish that relationship. Once that relationship has been established, I think we can go confidently into these phase III studies without repeating. So the ability to have this direct PD effect, we believe, gives us an opportunity to be a bit more aggressive with the late development design.
But you would say atopic derm is pretty similar to asthma and COPD in terms of dose recovery.
The reason why we are doing dose ranging in AD and in asthma is because getting into the skin and getting into the lung is different.
Yeah.
We want to make sure that you really need the same dose and the same degradation profile. I would say the AD is different from asthma, and AD is different from COPD. Maybe asthma is closer to COPD.
Yeah.
You can use asthma for COPD. I would not use AD for COPD, for example.
Okay.
In the phase I-B data, you had AD patient, but you also had asthma data along with it.
Yeah
With comorbid. Is there a chance that we could see similar data in phase II, or the patient population is completely different?
No. I think a large percentage of patients with AD will have comorbid asthma, will have comorbid allergic rhinitis. We had four patients that had comorbid asthma out of 22. That is about 20%, which is in the range of what is seen in the general population. It is actually usually a bit higher. I think it is 30%. I might be wrong. We definitely will have comorbidity. Again, I say it again, the comorbidity story for this program is critical. We will assess comorbidities. What we cannot do is do deep assessment of comorbidities because dermatologists are not going to do FeNO measurements in big global studies. There are other measurements that we will collect, and again, assuming success, we will disclose them in the right meetings.
Phase II enrolled really fast. You were able to push forward the readout by quite a few months. Is there a possibility to do something similar in phase III where you would expect faster enrollment, faster process, versus other trials historically in AD?
Well, obviously we've set an internal bar. The team knows that expectations for phase III will be that we roll fast. I'm not going to say how long it's going to take us, but we have used the information to project phase III, and obviously, again, I think we assume that in the presence of positive data, phase III should enroll even relatively faster because now we have placebo-controlled, randomized safety and efficacy data.
Let me ask, I know that the focus has been maybe to the more mild to moderate AD, but if you look at the moderate to severe end of things, is a DUPIXENT refractory patient the same as a SKYRIZI refractory? If you look at the different mechanisms, do you think that-
Just to be clear, we are still looking at moderate to severe patients.
Yeah.
Mild are not part of the equation. Again, the refractory to DUPIXENT, it's still a piece of biology that is not well understood. I think there are many companies, including us, that are doing studies to understand what happens. I think there are hypotheses. If you look at the literature, and you look at transcriptomic data of patients that have been on DUPIXENT for 16 weeks or longer, you see some upregulations of other pathways like IL-17, IL-22, in some cases IL-18. So there is, in some patients, some skewing from type 2, TH2 to TH1, TH17. Is that the solution? We don't know yet. I think there are studies that other companies are doing. There are combinations that we're doing in research to understand and explore whether we capture broader and deeper efficacy with combinations. So I think that story is yet to be told completely.
It's just odd that in I and I, you see sequential therapies for the most part. You don't see tons of combinations
Yeah
up front like you do in oncology.
I think it's just that immunology is behind.
Yeah.
I don't think it's the science. It's just oncology, because you're dealing with patient dying, I think there has been obviously more energy to try combinations. In immunology, most cases, you're not dealing with it, so there is more sensitivity to the safety. But obviously, it's happening. There is tons of bispecific and trans-specific.
Yeah.
Some of those will answer some of these questions.
Yeah. You good on 61? Okay.
Just last one on maybe for asthma. Is there a read-through from this trial enrollment to asthma? You could expect that faster enrollment, faster process, that we could see a similar result with asthma like being like-
I would say the reasons for the fast enrollment of AD has been patients, as I mentioned earlier, are really excited about an oral therapy. Investigators are excited about this pathway. They understand this pathway. We had exciting phase I data. In asthma, we have the same thing. We have excited patients, excited investigators, and interesting, exciting phase I data. The difference is in AD, we are enrolling into the broader population. In asthma, we're selecting for the high type two patients, and we have some pretty stringent inclusion/exclusion criteria. So actually, the funnel at the top is pretty- if you look across studies, obviously, I'm not going to share the numbers, but actually, the rate of patients that are coming onto our studies between AD and asthma are quite similar.
At the funnel, the inclusion/exclusion criteria, and the patients that drop off because of them is much higher in asthma versus AD. We'll probably still enroll fast, but not as fast as AD.
You good? Okay. All right, KT-579. HV data end of the year, maybe just give us some context for that.
Yeah. We'll have IRF5 579 data, and then we will have BROADEN2 data. We just put this out there for everybody to know. Do your homework on IRF5 first. Why are we excited about this target? As I tried to do it earlier quickly, there are very, very few programs in immunology where you both have human genetics data and biological clinical validation. The genetic says if you have IRF5 activation, let's say, you're likely to develop lupus, RA, Sjögren's, or IBD. Also, once we learn the biology, what is the biology of IRF5? If you block IRF5 and the pathway is activated, you see blockade of type I interferon validated in lupus. You see blockade of inflammatory cytokines, TNF, IL-23, again, validated in IBD, or you see blockade of B cell autoantibody production, validated in lupus and many other diseases.
You have the genetics kind of being the beacon, and then you have the validated biology that confirms the genetics. It's a very unique target. What we want to show, what we'd like to see in healthy volunteers, we can safely degrade IRF5, and that these three biological axes that we block in these preclinical models, can they be vetted in humans in these assays that we're going to use? And we expect between 50% and 80% reduction of these different cytokines and transcripts based on the biology.
Similar to KT-621, just looking for target engagement and the effect of that.
Yeah.
Okay.
Yeah.
Okay. Given, I guess, the mechanism, the downstream mechanism of a broader immune engagement for this, do you think that speaks to the difficulties of some of these diseases like lupus, Sjögren's? These have been a bit of a graveyard of development. Would you say IRF5 would be a more severe type of modality?
No, it is right. Obviously, there have been challenging areas driven by heterogeneity of patient populations.
Yeah
Sometimes challenging in measuring endpoint, high placebo rates. But in reality, there are mechanisms that have been really powerful. B cell-
Yeah
mechanism have been really powerful. TLR 7/8, which again signals through IRF5, have shown positive proof of concept.
Yep
AstraZeneca, Saphnelo, activity in lupus. I think it is about the mechanism
Yep
That capture the heterogeneity. We have a mechanism that captures many of these proven mechanisms. We expect that the power of IRF5 to again affect many of these proven mechanisms should be able to reduce the noise and increase the effect size in these patients. We are actually quite bullish about the study, understanding and being humbled by failures that have happened as recently also as a few days ago.
Just multi-organ systems.
Yes
make it a lot more difficult.
Yeah.
Yeah.
Yeah.
Particularly for Sjögren's.
Yeah.
Yeah.
For IRF5, I know you mentioned that you're going to present the biomarker data, and you're going to pursue lupus as one of the indication. Maybe talk about which kind of biomarker cytokine levels are more translatable to the lupus kind of studies. Are there any markers specifically that could help us determine kind of success rate in lupus indication?
Yeah. I think if we're able to show that we can block type I interferon in these assays, if we're able to see that we can affect B cell production of autoantibodies, I think that should give us the confidence that this mechanism should translate into lupus. If we show impact on TNF IL-23, should give us the confidence we can go into IBD. That's how we're thinking about it. Again, it's not only these. If we were just some ex vivo human volunteer assay, I don't think that's enough data. But it's obviously the totality of this data with the genetics, with the preclinical data, and this confirmatory data that gives us the confidence that we should move into these patient populations.
Is there anything that you could see in the data that would convince you to pursue both lupus and IBD simultaneously at a certain point?
Yeah, as I said, as long as we demonstrate the activity that we are looking for. Again, I cannot speak to timing of it, but yes. I do not think we are interested in sequential development. I think that is a thing of the past at this point.
Yeah, just along those lines, too, a lot of these are unmet needs, right? A basket would make sense here as well, but there is less understood about the biology and its broader deployment of the mechanism.
Yeah. Obviously, Geoff loves basket trials. You have said it twice already now.
Right.
No, it's good. I think that they are interesting when you have small population that are tied by similar biology. I think the concern we have with that, and I'm not saying it's not a good idea, is the signal-to-noise in these diseases is so small that we need to really think through how do we make sure we have the right bar to hit across these diseases, and whether it's easier to do individually versus together.
Are you comfortable with where FDA is on some of these, like accepted endpoints and Because it's been a challenge, right? There's been so many failures.
Yeah. I think the regulatory environment is evolving, right? I think we're trying to use other composite endpoints, especially in CLE, right?
Yeah.
When we've seen recently with CLASSY. Now, I think there is innovation happening there, where we can look in more than the traditional endpoints, which have been difficult to hit for all sorts of reasons, because these are complicated diseases with different biologies. I guess we'll see how-
Yeah
things evolve.
Are there any learnings that you could carry forward from your KT-621 healthy volunteer study to phase I, how you conducted the AD study for this IRF5 program? Just trying to get a high level thought on what you could take forward from that study into-
Yeah, I think high level, the strategy that we're trying to adopt for IRF5 is actually quite similar. Healthy volunteer to confirm the molecule does what it's supposed to do. A small-ish biomarker study to confirm that the biology is doing what it's supposed to do in patients. Then a dose ranging study to fully demonstrate that the molecule and the biology leads to the efficacy that you need. So, in a way, we're trying to follow the same path, but obviously different diseases and different endpoints.
Let's talk, I guess, more broadly about the discovery effort. The goal you guys have had is one new target on an annual basis. How much of the effort really is in the preclinical discovery effort? Are there targets that are mechanistically, and could be clinically distinct from what you have-
Yeah
but related to the same TPD?
Yeah, we have 100 plus people in our research group, so we're definitely putting a lot of effort into continuing to build a pipeline. As you know, our ambition is to become an independent commercial company, and the only way that you can justify being a commercial company is if you have a real engine of innovation that continues to fill the clinical pipeline, that you can use your commercial team synergies to commercialize. Otherwise, we're just reinventing the wheel here. We have tons of biology that we're investigating. Some is, as I mentioned earlier, what is the right potential down the road, combo opportunities to broaden and deepen our responses in many areas we already are in, and some are completely complementary areas that we're going with degrader technologies and beyond degrader technologies.
As you know, we are an oral immunology company and not defined by one modality. As we continue to grow, obviously, we tap into what we believe our strengths are to deliver innovative medicines.
Is there a strategy to I know you guys have moved away from oncology, but there's a strategy to leverage the knowledge base at Kymera to, if you have others or outlicense or-
Yeah
I know you have the Gilead partnership, right?
Yeah. No, it's a great question. The technology's disease agnostic, and I am committed that once we demonstrate to all of you that we can do end to end in a disease area, let's say immunology now, we can launch six to one, then we earn the right to do more.
Yeah
I think it's distracting to play the game that we can do everything. I think that's how companies can do bad things. So we're preparing for what that other diseases could be. In the meanwhile, yes, our creative scientists have unique insights sometimes, and if they're not right on strategy, then partnering could be an opportunity to maximize their value. That's what happened with CDK2, and I will say we have other programs that might lend themselves to that type of strategy, but it's not our focus.
Okay. Awesome. Guys, we're out of time. Thank you very much.
Thank you.