Good morning to everyone in the room and on the webcast. My name is Fasiq Rashid. I'm one of the senior biotech analysts here at Jefferies. Really pleased to kick off this first morning of the Jefferies Global Healthcare Conference in New York. We're starting today with Kymera Therapeutics. I have on the stage with me Dr. Nello Mainolfi, CEO and co-founder of the company. Nello, could you start by introducing the company as well as the journey that you guys have been on now that you're 10 years into the founding of the company?
Well, thanks for the invite. Great to be here. Let me start with a bit about Kymera. We just celebrated a 10-year anniversary. We started the company with a simple and ambitious idea, using a new technology, targeted protein degradation, to develop a whole new generation of medicines that will go after targets that have been historically undrugged or poorly drugged, in pathways with high degree of both genetics and human validation. It's been an amazing journey of build, of learning, of evolution, of refinement of our strategy. I think we're in a very unique spot right now. We have, I think, one of the most exciting programs in the industry. I think the most, but obviously I'm biased. We have a program like KT-621 against STAT6, which has the potential to impact millions of patients around the world that have type 2 inflammation.
We're in two global Phase IIb studies. We have, I think, one of the most interesting target in immunology with IRF5, where we're targeting an undrugged transcription factor that is known driver of disease, lupus, IBD, et cetera. We have two really productive collaborations with Sanofi and Gilead in both immunology and oncology. Actually, I would say almost more importantly, we continue to innovate, which is a must at Kymera. We have a rich preclinical pipeline full of exceptionally interesting programs that we look forward to sharing as they enter, usually IND-enabling space. That's where we are today and the best is ahead of us.
Let's start with BROADEN2. I know you guys are not going to give a play-by-play on the study, but in terms of the enrollment period of the study, we're at the halfway mark, given when you started and when you've guided to completing enrollment. Can you talk to us at all about how it's gone so far and if you feel like you're on track?
Yeah. The BROADEN2 is our phase IIb study in atopic dermatitis with KT-621. Just to remind everybody, KT-621, as I mentioned, is a STAT6 degrader. We've shown that by degrading STAT6, you're able to block IL-4 and IL-13 signaling. We believe we've shown as well as upstream biologics, whether it's Dupixent or others. That has put this program in a very unique place, which is the uncharted territory of oral drugs with biologics-like activity. The BROADEN2 study is a global phase IIb study, dose-ranging studies, where we have two important goals. One is demonstrating in a placebo-controlled, randomized large study, the efficacy and the safety of the drug, as well as almost as importantly, selecting a dose to proceed into registrational phase III study. We started enrolling the roughly 200 patients that we set out to enroll. We started in late last year, late 2025.
We expect to complete enrollment by the end of this year, with data by middle of next year. We're on track, as I said earlier. I think we've said publicly now, I believe a few times, that we are going to give an update when we've completed enrollment. Until then, we probably think it's responsible not to provide other updates.
Got it. In both phase II-b studies, BROADEN2 and BREADTH are dose-ranging studies. Can you talk to us about what went into selecting the doses for the studies? Is it the same doses selected for each of the two phase IIb studies?
Yeah. The BREADTH study, if you don't mind.
Yeah
quickly clarify. The BREADTH study is a phase IIb global study, evaluating KT-621 against placebo in eosinophilic asthma patients. The 2 studies use the same three doses + 1 placebo, so it's 1 to 1 to 1 to 1. The beauty of targeted protein degradation, and I think it's one of the most important compelling reason why this technology has disruptive potential, is because you can actually understand the level of target engagement at any given time with your drug. We dosed more than 200 subjects in our healthy volunteer study or generally in the phase I study, to actually understand what is the level of degradation that corresponds to the exposure that corresponds to the dose. When we selected three doses for the phase IIb studies, we had simple questions.
Basically, based on preclinical data, we know that more than 90% degradation leads to a pathway blockade that is similar to one of upstream biologics. We feel like that is the pharmacological dose. The question is, what if you go slightly above or slightly below that dose? What is the level of efficacy and safety that you see with that particular paradigm? This was our dose selection process.
Got it. From a regulatory perspective, as you think about providing a sufficient evidence base to support phase III dose selection, do you have to show a dose where you have slightly less efficacy to show that you have truly interrogated the correct dose?
Yeah, I think ideally, out of the three doses, you would like to show that one dose has less pharmacological and clinical effect, so that you've shown that you have interrogated the biology and the clinical response as well.
Got it. Would the goal be to have a single dose to move into phase III? I guess it's a nuanced question because the question is, would you have the same dose as well in the derm diseases and the respiratory diseases?
Yeah, great question. Maybe the first part first. Obviously, it would be ideal to select a dose, one dose. It will make the phase III design, and also probably timing of enrollment, et cetera, I think much faster. That does not mean that having two doses is bad, it's just obviously more complex. Ideally, it would be one dose, but we'll be data-driven and we'll make a decision with data in hand. The answer to your question about will it be the same dose in AD and asthma, so that's a great question, and I think it's a question that we'll answer with data. At high level, we have seen pre-clinically that we see consistent degradation across all relevant tissues. That has basically allowed us to project that probably the same dose would be as effective across diseases.
The answer that we'll only know with data, will be, do you require more or less degradation in different diseases? If that is the case, let's say you require more degradation in one disease and less in other, in that event, it's possible that you'll end up with two different doses.
Got it. Then, jumping in more deeply on BROADEN2, the phase IIb in atopic dermatitis, you were telling me that you've been spending a lot of your time on the operations of the study and visiting the study sites and doing things like that. Could you talk to us about what gives you confidence in the company's execution capabilities for this very important study? What you're doing to avoid some of the common pitfalls in this disease and even what those pitfalls are.
Yeah. Obviously, I think it's fair to say that this is the most important study that we've run at Kymera, everybody's really focused on excellent execution of the study. There are a few things to keep in mind. What are we trying to protect from? Mostly trying to protect from an execution of the study that might lead to higher placebo rates that might obviously eat into the depth of efficacy that you see. That is because that has been seen with other studies, let's say, in the past five to 10 years. Now, the reasons for these increased placebo rates have been mostly driven by one fact, which is the patient population that is enrolled in these studies is a bit less severe than it was in the early days when there were no systemic drugs approved.
Naturally, with the less severe population, you have more disease fluctuations, and you'll have more placebo rates. I think that's not the only reason. Some of the other reasons are high. It's a highly competitive space, so there is competition for sites, for patients, for attention. When there is competition, often, sometimes, quality can be impacted. Having a process where you can ensure you have the right patient on the study, you have the right oversight on the CRO and on the sites, that you have oversight on the quality of data that you monitor daily, is I think what's required to ensure highest quality of outcome. That's what we've all been focused on.
My involvement is mostly to obviously continue to speak about the opportunities with this program, to make sure that there is knowledge, excitement, hopefully, and awareness in the medical community, in the investigator community, and I think it's the responsibility of the company to do so, continuously, actually, not just now.
Got it. With respect to other studies in the atopic dermatitis landscape, there's at least two things that are unique, and I'd love to hear if there's anything else that you would point out as unique as well. One is that obviously your drug is an oral drug, so you have oral placebo as well. The other is that your study actually allows prior IL-4 and IL-13-targeted drugs as long as patients didn't fail those drugs. Could you describe those features a little bit and also tell us, are those features that are expected to change the placebo rate in either way, up or down?
Yeah. I don't expect the way the drug is administered orally versus sub-Q or IV to have any impact on placebo rates. Again, I think the placebo rates are mostly impacted by the patient's characteristics and baseline, as well as by quality of execution. With regards to prior exposure to biologics, I think what we're doing is the probably most rational thing to do, which is KT-621, which is a type 2, I think potentially the best type 2 drug, is targeting IL-4 and IL-13. We expect that a drug like KT-621 should be first in line drug for all patients with type 2 inflammations, not just AD, but other diseases and their comorbidities.
We obviously welcome patients that have been on pathway drugs that have had response to them because that obviously will explore how well patients will do if they go from one injectable to an oral. I don't think it's the time where we need to explore the refractory patients because we don't believe that's where the medicine would be placed in the treatment paradigm.
Would it be fair to assume that by allowing those patients, you might actually help mitigate against some of the risk of higher placebo effect?
Yeah, that's actually an interesting insight. I think if you have a patient that has responded to a drug of this pathway, that means that that patient is sensitive to anti-type 2 inflammatory drug. I'm not sure, again, that that will necessarily impact the placebo rates, because again, those are impacted by so many other factors. For sure, I think has an opportunity to increase the signal-to-noise ratio.
Now that you're well into the study enrollment time window, can you talk to us about your expectations going into the study for baseline EASI, and if those expectations have changed now that you've seen the profiles of some of the patients coming in?
Obviously I'm not going to comment on what we're seeing. If you look at our phase I-B study, I think our mean EASI at baseline across the two doses was around 25. That is somewhat consistent with many studies that have been run. Recently, I think you see I'm talking about good studies. There are studies where baseline EASI is 20, which probably they're not good studies, but 24, 25, 26, it's probably generally the norm. Again, that's our expectation. We'll see where we land. Again, we've deployed some I think quite sophisticated approaches to ensure high patient quality. I'm actually quite curious to see where that will lead us with regards to patient severity and patient quality.
Got it. On the specific things that you're doing from an execution perspective, could you at least maybe hint at, do you believe that what you're doing is substantially different from what other companies in the space have historically done?
I would say that way, what are the parameters that you can control? At least you want to try to control. You want to ensure that patients that enroll into your study have atopic dermatitis, which surprisingly is actually not a given. You want to ensure that patients on your study are actually moderate to severe, which is also not a given. You want to ensure that the investigators that rate your patients are consistent and are experts and are trained, and then that sites and CRO and Kymera has close oversight over the study conduct. Those are the parameters, right? The rest, it's biology, drug luck. The things that we can control, I think we are doing everything that we think is humanly possible to do it in a way, obviously, to retain study integrity.
I would be surprised if there is any other company that is doing anything that is more innovative than we are.
Got it. On the safety side of things, what are the key safety events that you are just looking out for this drug class in general?
Well, we are at the forefront of this drug class, I can only go back to what we have experienced so far. What we've seen so far pre-clinically, we've run so many tox studies, two weeks, four weeks, four months, six to nine months. We've actually run the whole gamut of pre-clinical safety. In all studies, I've never actually probably seen that ever in my career, we have not seen any adverse findings in any studies. In the phase I studies, we had healthy volunteers with placebo and AD without placebo against placebo-like safety, I would say, probably across the board. Based on pre-clinical data, we don't have anything we're on the lookout for, and based on clinical data, we haven't seen any emerging pattern. It's hard for me to say that we're on the lookout for anything.
I would say we're on the lookout for everything. We're obviously monitoring, the team is monitoring safety very closely. We'll see.
Got it. One of the features on the safety side that's seen for the IL-4, IL-13 biologics is conjunctivitis. Can you talk to us about how do you see the risk of conjunctivitis for KT-621? Is there any biological reason for this to be any better or worse than what we see with IL-4 and IL-13?
I think what we know is patients with AD have conjunctivitis, and then what we know is that if they take an IL-4 and IL-13 drug, they seem to have more conjunctivitis than in the placebo group. I think that's the fact right now. The percentage of conjunctivitis that you see across studies varies. I'm personally not convinced that all these drugs in this pathway, whether it's Dupixent, it's Ebglyss, and others, have different rates of conjunctivitis. I think there is a very stochastic aspect to this. Generally, I think they're in the same general ballpark is my interpretation. I might be wrong.
Let's say they're in the general ballpark, and again, it's the phenomenon of having conjunctivitis and then on top of it, this drug class seems to increase the rates by, let's say, generally 10% or so, 10%-15%. What I can say for STAT6 is so far in the phase I-B in patients, we have not seen conjunctivitis. Remember, we had 22 patients, dose for 28 days. If you look at Dupixent, 28 days, the rates of conjunctivitis were within the 5%. It would be like one patient at worst. The fact that we haven't seen it yet, I'm not sure tells us that STAT6 targeting does not lead to conjunctivitis. My base case is that we will see it, and then I think if we don't see or we see less or more, will be something we'll have to wait for the data.
Got it. Within the atopic derm competitive landscape, what are you paying attention to more or less within the competitive landscape?
Oral or in general?
Just in general. I know what investors ask me about, but I'd love to hear just as you look into the landscape, as you go to medical conferences.
Yeah
What are the specific drugs or specific mechanism classes that you guys have on the radar and are looking at?
I've been at both the EADV in the fall and AAD now in the spring, I guess. I think KT-621 was one of the most exciting drug in the clinical landscape. That's not what I'm saying, but what has been discussed extensively by KOLs and presenters. That I know I'm paying attention to. I like innovative things. I like understanding how we can get the AD disease be responsive to a therapy like we've seen in psoriasis. Psoriasis is a much more homogeneous disease, and we've learned that if you hit IL-23 or IL-17 or the IL-23, 17 biology axis, you can basically cure most patients. AD is nowhere near that. We know it's a Type 2 skewed disease, but obviously there is more than that, right? We obviously don't see 100% EASI scores, at least not dramatically.
I'm very curious about novel mechanisms that are asking the question of what's happened to the remaining patients, whether alone or in combination is what I'm interested in. Less interested in incremental changes to existing drugs.
Got it. Within the STAT6 landscape, there's another STAT6 degrader that is, I believe at the stage that you guys were at, call it like 18 months ago. Other than the timing difference.
Who is that?
We don't have to name drop.
Okay
on the mic. It's okay.
Okay. It's all right.
Other than the timing difference, can you comment on how you see that program as similar or different from yours?
I think 18 months, 621 was still, 18 months ago, still the best molecule. 18 months later, we're still better than others. No, besides the joke. I know there is a couple of degrader programs that are, as far as I understand, in IND-enabling studies. We just don't know enough about these molecules to have an opinion. Again, our data is out there. We've been presenting in conferences. We have a couple publications that we're writing. It's very easy for our, let's call it competitors, although many of them are friends, to being able to demonstrate their activity versus Dupixent, and in that way compare to 621. I look forward to seeing that data from other companies so we see where these molecules stand.
I think we have a drug that degrades 90% at least at any dose above 1.5 mg once a day with placebo-like safety. It's hard to know what you can do to make another drug competitive.
Got it. I want to shift gears to talk about asthma a little bit. I think this is a topic that investors are not talking about or thinking about enough. Can you give us just overall high level the pitch on KT-621 and asthma?
Yeah. I think the most impactful thing for KT-621, I believe strongly that this is a Type 2 drug that will impact all the diseases of people with Type 2 inflammation. It's not just an AD drug, for as much as AD is a huge disease. I think the unmet need in asthma, I would argue, is actually even superior, not because in asthma they don't have effective drugs. They actually have many more drugs than AD. All systemic effective advanced drugs are reserved for what is called GINA five, meaning you have to go through four more steps of treatment, which include bronchodilators, include corticosteroids, either inhaled or systemics, that actually have deleterious effect, especially on children.
It's actually quite difficult to accept that in order to have a drug that treats the underlying inflammation, you have to go through years of being treated with drugs that do not affect the underlying inflammation. I think the opportunity we have is to change the treatment paradigm. My dream would be that KT-621 would be the drug that you're given as soon as you're diagnosed with eosinophilic asthma, meaning you have IgEs. More likely when you have IgEs, you have high FeNO, but you have a number of EOS that tells you you have eosinophilic asthma, and you should be on that drug instead of drug that don't treat that disease. That is a huge population.
Got it.
That is not served right now.
Yeah. Your phase I-B study was in atopic derm. Give us an idea for the extent to which you feel the atopic derm phase I-B de-risks your asthma development program.
Well, we've shown extensively. Do we have five more minutes or we're done?
Yeah, we're good.
Okay.
We'll-
I was just watching the time.
We'll go quick in these last five.
Yeah. No, I was just checking because I thought it was almost done. What we've shown preclinically is that we are able to impact type 2 inflammation in lungs, in skin. Actually, we have also other data in other tissues. In the phase I-B data, not only did we show that based on biomarkers we block all these type 2 biomarkers that are relevant to AD, asthma, and other diseases, but we also had a few patients with comorbid asthma. We had a few patients with comorbid allergic rhinitis. We had 14 patients out of 22 with comorbidities, and we've shown in all of them that we were able to impact their comorbidities, both asthma and allergic rhinitis, showing that our drug gets into the upper airways or lower airways, block the inflammation, and have initial, again, initial impact on disease presentation.
I think that is huge for a drug that mechanistically is supposed to do that. The fact that you demonstrate that makes you very confident.
Got it. We have four minutes left, so maybe we'll try to rapid fire go through a few of these. You have Fast Track designation for 621 in both AD and asthma. Can you talk to us about what benefits does that confer, and is a Breakthrough Therapy designation a possibility for this program?
Yeah. The Fast Track allows us to actually engage with the FDA more frequently to ask questions and to talk about plans and strategies that we have in place, and this is something that we're fully trying to benefit from. The Breakthrough Designation is a good question. I would like to think so. Obviously, Dupixent had Breakthrough Designation as the first systemic drug in AD. I think we might have an opportunity as an oral drug with the safety and the efficacy that we hope we'll have, but it's not on me to make those decisions. I would like to think that that's possible, but unfortunately, I don't make that decision.
Got it. Then just briefly on the IRF5 program, you're going to have phase I data later this year. Can you set expectations for what would be a positive outcome in that dataset?
Yeah. I'm super excited about IRF5. This is definitely a program of potential big impact in diseases that don't have good oral drugs. Lupus, almost no good drugs, although some new are being approved now that have exciting efficacy, but not oral good drugs. I think we have opportunities in IBD, potentially RA, to go after patients that don't really respond to first-line therapies. More importantly, we have a new axis that we're targeting, thanks to protein degradation, that is the central node of multiple inflammatory pathways. What we want to show in the second half of the year is strong degradation. We like to go beyond 90%, as we always do. We might not need it for that target, we still want to get there.
We want to be able to show, obviously, that the safety is consistent with our expectation, and that through this ex vivo assay, we can block pathway cytokines as we've seen pre-clinically, so that we can tie the genetics, the biology, with the potential clinical translation into patients.
Got it. Just one final question to wrap us up here, Nello. You're going to have meetings for at least part of the rest of the day here. What is one investor question that you wish you didn't get anymore, that you hear the question and you think, "Oh, man, I wish I don't have to talk about this anymore"? What is one investor question that you feel like people don't ask you and you think, "Oh, I wish people were asking me about this"?
No, I think one question, I think talking about beyond AD, like you just did. I think you're the first one in a while, if ever, that want to talk about asthma and the asthma opportunities. I think that is a topic that I love to talk more. I don't have questions that I don't want to hear. There are questions that we've been discussing for a while, or questions that could've been asked 10 years ago. We're here to answer questions, and I think it would be really a bad attitude not to want to answer questions, so we're here for that reason. Did you have a third question?
No.
Okay.
That was it.
Pretty politically correct answers.
Yeah.
Very unlike me, actually.
No. I try asking this question. My hit rate is not good for getting a very candid answer to it.
Yeah, I know. In this setting, it's hard to answer that question.
Got it. Okay. Well, thank you so much, Nello, for joining us. Thank you to everyone who's dialed in