Great. Good morning again, everyone. Thanks for joining us for the next fireside chat. We have Kymera Therapeutics CEO and Founder, Nello Mainolfi, and CMO, Terence Rooney, for our fireside. Maybe I'll kick it over to Nello for a quick overview of the company, and then we'll dive right into a Q&A. Nello, over to you.
First, good morning, everybody. Alex, thanks for the invitation. Kymera, founded 10 years ago with the goal of advancing a whole new class of medicines using targeted protein degradation, which is a small molecule-based modality that allows us and others to completely, if necessary, remove disease-causing protein from their intracellular localization. We have spent the past decade optimizing few areas of the company. Target selection, what are the right targets for protein degradation? What are the right diseases? What are the right molecules? And how do we both identify first and then develop these small molecules that specifically and selectively degrade disease-causing protein? We spent the past six years focused almost solely in immunology, and we built a wholly owned pipeline of first-in-class programs. We have a STAT6 degrader in a couple of phase II-B studies with one of them reading out actually quite soon.
We have another first-in-class program, IRF5, for which we'll share phase I data also soon. These are both transcription factors traditionally undrugged. Then we have a couple of actually high impact partnerships with Sanofi and Gilead that obviously we can talk about if there is time.
Great. Yeah. Obviously, I think a lot of focus on KT-621, your STAT6 degrader. The big news earlier this year was moving your phase II-B readout to the end of this year from by mid 2027. I guess sort of what drove that change, and should we infer anything really from that speed of execution for sort of the uptake or sort of excitement around KT-621?
Yeah. As you know, Alex, you've followed the company for a while. We're very passionate about what we do. Obviously, that's often not enough to move timelines like this. I would say that there are four key reasons. One, patients are exceptionally interested in oral molecules for type 2 diseases. We're seeing in both AD and asthma. Because these advanced systemic therapies have really low penetration in AD, about 5% in the whole moderate to severe patient population in the U.S. So that's patients really want an oral medicine. Two, investigators, I think globally we can say, I think there is a high level of interest and comfort with this mechanism. It's in a pathway that is very well understood and studied of well-characterized safety and efficacy, and expectation that a drug like ours could potentially deliver that type of interesting safety and efficacy profile.
That obviously makes our life easier if investigators are excited about this program.
Third, I would say that we generated some really exciting data, as you know. Both pre-clinical and early clinical. Then fourth, we as a team really did everything we could to be really all over the world meeting and presenting Kymera at both medical meeting, investigator meetings, at sites, so that everybody understood how serious and how committed and passionate we are-
Yeah
about this program.
I guess what gives you the confidence that you're not sacrificing trial integrity or conduct for speed here? Can you talk through what are the elements of your phase II-B that give you confidence that the trial is not going to fail the drug?
Yeah. I would say that the trial enrollment has moved fast despite all the measures that we put in place. In fact, the goal was never speed for us. Obviously, speed is important, but our goal has always been quality over speed, and never compromise quality for speed. That makes actually the pace of enrollment much more impactful. So what we wanted to do is ensure that we would get as high quality data set as possible. Obviously, we can't control efficacy-
Yeah
and safety, but we can control the integrity of the study. So we wanted to make sure patients on our study had the right diagnosis and the right severity. We wanted to make sure our CROs and our sites had the right level of oversight on the patient flow and quality. Patients also, how stable they were on their emollients and/or prior therapies was something we spent a lot of time on. So we had put all these measures in place, some of which I don't think any other biotech has done before, ahead of starting the study. And actually, we thought that it would negatively impact the enrollment. So I would say that we moved quickly despite the measures and not that we moved quickly because we wanted to just move quickly.
And then one of the other unique things in this study is that you're including adolescent patients as well, which is sort of unique relative to other contemporary AD studies in this space. I guess, can you talk about the rationale for that and any implications for thinking about the clinical efficacy data set?
Yeah. Maybe I'll touch high level, and I'll pass it to Terence. So high level, we are committed to the pediatrics population because it's actually a key target population for drugs in type 2 diseases. That's the main reason. But I'll let Terence speak to maybe your answer more specifically to your question. Sorry.
Yeah, on the pediatrics. So hey, Alex, great to be with you today. Safe, effective oral is we're hearing a lot from the adult community as we interact with them, both as investigators and patients in the trials, and dedicated market research, that there's a huge appetite for a safe, effective oral. A lot of people are on the sidelines not accessing today's advanced therapies because they feel that an injectable therapy or an oral therapy with multiple box warnings is not for them. It's a psychological barrier they're not willing to cross. It would feel to them like too big a gun for the disease that they feel that they have. That is, for a small minority of those people, true needle phobia is also an issue.
I will say that we hear this even more clearly in the pediatric community for children and their families, where the fact that injectable therapies are associated with needles is in and of itself an even bigger factor.
Yep.
We do pediatric development generally around the industry because it's a regulatory requirement, because it's the right thing to do. Usually, quite often, not for commercial reasons, often our pediatric programs associated with adult diseases are not commercially of strong relevance. That's obviously different in type 2 inflammatory diseases, where not only is it a regulatory requirement, not only is it the right thing to do and there's huge appetite in the community, it's also a significant commercial opportunity because type 2 disorders are so prevalent in children compared to adults as a general proportion. That's the setup for the direct answer to your question.
Yeah.
We're looking to do as much pediatric development as in parallel as possible, in partnership, obviously, with regulators.
Yeah.
You've started to see a bit of that in that we have adolescents embedded in our phase II-B study. You can expect to see the same in our registration program, and then we'd look to move to younger children as quickly as we reasonably can.
Yep. Makes sense. I think the question that now I know you'd love to answer is what does good look like here? How should we interpret, I guess maybe the phase I-B data where all of the data so far suggests that this should look like DUPIXENT? We have the mechanistic rationale, we have the phase I-B data. Shouldn't this look like DUPIXENT in the phase II-B? How are you thinking about that in terms of an outcome?
Yeah. No, thanks for the question, and I think it's also an opportunity to clarify a couple of things. What is a successful drug in type 2 diseases, and then what are our scientific expectations?
Yeah.
I know we have limited time. I am going to try and cover both quickly.
Sure.
I like how you want to move to the next question. Actually Terence mentioned it. We have done a ton of market analysis. There is about 6 million- 9 million patients with moderate to severe AD in the U.S., 400,000 are on advanced systemic therapy. It is about 5% penetration. We clearly have an opportunity to expand these markets.
Sure.
This is a very early market. When you ask patients and prescribers what would change the penetration, safe, effective oral does not have to look like injectable biologics. Comps, Otezla, 50% the efficacy of biologics, multibillion-dollar drug. Icotinib, 20%, 30% less efficacious than biologics. I think our colleagues at J&J are having one of the best launches and mobilizing new patients. What does success look like for a drug like KT-621? Safe, effective. It does not have to look like DUPIXENT. We believe that is going to be a commercially successful launch, and obviously revenues from there. If you ask me where is this study going to land, I agree with you. I think it is going to land into that dupilumab range.
I like to call it ballpark, because all the data of the past five years, or at least we have shared externally since January of 2024, has said that we block IL-4 and IL-13 as well as in upstream biologics. We impact biomarkers in patients as well as upstream biologics. We change itch and lesions as well as upstream biologics, even though it was a small uncontrolled study. It is hard for us to say no, it is going to look now magically way better or way worse. It is going to be in that range. That is our expectation.
Yeah. That makes sense. I guess sort of the other element of this study that's unique is you tested two doses in the phase I-B, right, 100 mg and 200 mg. They didn't look all that different, but it was a good way for you to understand PK and STAT6 degradation in patients. How should we think about the dose range that you're studying in the phase II-B, and how important is it for you to show a dose response in this study? How should we interpret that sort of totality of the data?
Yeah. Just to be clear, in the phase I-B, we chose 100 mg and 200 mg, not expecting them to look the same, right?
Yeah.
We actually wanted to check whether they will look different, and in fact, they didn't, as expected.
Yeah.
When we went into this study, the study was not designed to show dose response per se, right? It was not perfectly designed. We could have picked the lowest dose possible and the highest dose possible, and something in the middle will show beautiful dose response. The goal was, let's find a way to select the best phase III dose. Our strategy was the following. We thought of picking a mid dose that we believe hits the right pharmacology, that we believe is required to see maximal efficacy. Then we chose a higher dose just to make sure, on top of it, just to make sure we weren't leaving things on the table. Then we chose a lower dose where we expect to see less activity.
We obviously don't know what things are going to look like, but I wouldn't be surprised if we saw the top two doses being much closer to each other than that lower dose.
The other open question here is safety. I think the on-target question might be conjunctivitis, and then obviously you have questions around idiosyncratic small molecule tox, and then potentially maybe platform questions. I guess, among those three buckets, maybe let's start with conjunctivitis and your thoughts on whether you might see that with this mechanism or not.
Yeah. Our view has been this drug blocks IL-4 and IL-13, as I've said already 5 x, as well as-
Yeah
upstream biologics. If blocking IL-13 seems to be associated with conjunctivitis, we'd expect to see it. In the phase I-B, we didn't see cases of conjunctivitis.
Yeah.
In reality, it was a 28-day study of 22 patients. If you look at rates by four weeks, it's about 5%, so one patient. Did we just not see it, or it's a sign of a different profile? I think this study will tell us. Again, my expectation, I've said this for years now, that we would see it, but we'll see. Do you have the other two?
I guess sort of, at a high level, small molecule idiosyncratic tox or potentially, the question around the PROTAC platform in general, whether or not this type of degradation could ultimately be toxic. I guess sort of on a broader safety profile perspective, can you speak to sort of what you've seen pre-clinically and
Yeah
in phase I?
Yeah. We have eliminated STAT6 from animals for years now.
Yeah.
Our longest study was in non-human primate, nine months. These monkeys had no STAT6 for the duration of the study, and we'd seen no adverse events whatsoever. So adverse findings, actually, it's technically said for pre-clinical studies, my tox guy keeps telling me. No, we didn't see adverse findings, which I think speaks volumes about the specificity of the drug and the safety of STAT6. I don't think there are any platform safety questions. The degradation of protein has actually been happening for decades, unknowingly or unknowingly with other drugs, and we know that there isn't anything special about degrading protein. It comes down to the target of interest, and it's the safety of the target. The reality is this is still a novel target in a pathway that is well understood.
If the biology is the same that we understand and hypothesize and have demonstrated, we expect to see a safety like has been seen with dupilumab. Our job is to continue to explore, verify, and validate as we do longer studies, bigger studies. This is going to be a big event because it's the first time that we dose 200 + patients for at least 16 weeks. Obviously, I think we'll have a very good sense of the safety profile, much more than, 22 patients for 28 days or 200 healthy volunteers for up to 14 days.
Great. Maybe here I wanted to pivot to, you're running a phase II-B asthma study as well. Can you speak to, as you think about the type 2 space, your indication expansion strategy here?
Yeah. Terence, you want to take that one?
Sure. Alex, as you might imagine, the first ungating event will be the Q4 readout of BROADEN 2.
Yeah.
All being well, as you also might imagine, that would ungate a registration program in atopic dermatitis. Where are we with that prep? We are waiting with bated breath for the results, but we are not waiting to prepare for phase III. The superstructure of the phase III program is well defined. As you might imagine, it is heavily informed by our colleagues around the industry who have taken assets all the way in atopic dermatitis.
You might imagine thinking ahead, there won't be too many surprises in the general structure of that phase III program. We are also far ahead down into the details of protocol development in the kind of line-by-line step, and we are far advanced in the operational prep with vendors and other elements of the mechanics of making sure that those two key intervals after readout are as small as possible.
From opening the envelope to our visit to the regulator for an end of phase II interaction, and from the regulator to opening that first site, screening that first patient, dosing that first patient. You have heard guidance from Nello and others that we are on track for that to happen mid-next year. What else might that event ungate? Well, it could ungate other dermatology indications in the type 2 space, and you can imagine what they might be.
But we also think we will learn enough to ungate gastroenterology, and obviously in this space, that is eosinophilic esophagitis. We like the look of that indication a lot, and we are far advanced in preparations for a registration program there. We will also learn a ton about the probability of success and dosing in the respiratory indications. But as you said, we are running a mid-phase trial in mild to severe asthma. It will readout next year. Before we actually unleash any registration programs in respiratory, we'll want to see those data. But in the meantime, we're very actively prepping for asthma, for chronic rhinosinusitis with nasal polyps, and potentially other indications that might include COPD and others.
Yep. Totally makes sense. And I think this gets at the breadth of the type 2 opportunity, the number of indications you could explore. DUPIXENT's approved in nine currently, and there's more that you can consider. I guess, given that landscape, Nello, what is your appetite for going it alone if BROADEN2 works, if asthma works? How are you thinking about what does Kymera look like 5 - 10 years from now?
Yeah. Look, there are, as you said, nine indications. In reality, about five indications are 90% + of the revenues. As Terence was saying, we are preparing to engage in registrational studies across those four or five plus indications. So, assuming we can continue to fund the development of this program, which I think will mostly depend on the quality of our data. I think now many biotech companies have shown that you can build both successful late development and commercialization organizations that can maximize value creation. So we are planning, our base case is go along all the way, and we're seriously planning both the development and commercial strategy.
At the same time, as we said publicly in the past, I think after this phase II-B data, it is reasonable to explore if there are parties that are able to potentially accelerate or broaden or help to de-risk some of the late-stage commitment, mostly commercial, maybe less clinical. And we have high expectation and high bar, so we'll see if that's possible. But we'll do the responsible thing to do to maximize patient impact and shareholder value.
Makes sense. I do not think it will do it justice, but in the last few minutes, I really do want to touch on KT-579 IRF5, which I think falls into sort of this emerging space of innate immune biology and rheumatologic disease. I guess maybe as a stage setter, curious how you think about IRF5 as a target relative sort of to other targets in this space, like TLR7/8. What got you excited about IRF5?
Somebody told me yesterday, "Do you guys realize you have the two hottest target in immunology?" I think everybody realizes that STAT6 is, but probably not everybody has yet to fully appreciate the opportunity with IRF5. This is a key node of multiple pathways that have been extensively validated, type I interferon, inflammatory cytokines like IL-23 and TNF, B-cells, and it is all the autoantibody production. So when IRF5 is activated, it has a profound anti-inflammatory effect.
We know that the genetics are pointing us to this. They are pointing us to discrete diseases that we want to go after, SLE, IBD, Sjögren's, RA, potentially. So this is one, again, another transcription factor that has lots of literature, but no drug development associated with it, and we will be the first company to show. We will have data actually relatively soon ahead of the BROADEN2 data, we will disclose the IRF5, and we are exceptionally excited to then hopefully be moving this program into a patient study soon thereafter.
So SLE, is that clearly your first PoC at this point?
Yeah. Terence, you want to speak to that?
Yeah, I think you could. We're thinking of replicating the STAT6 playbook-
Yeah
moving into probably a concise biomarker-focused proof of mechanism study in patients. SLE would be high on that list for sure, given the genetic links and the strong biology where the pathways downstream of IRF5, like type I interferon, like B-cell autoantibody, have been clinically validated through monoclonal antibody targeting in lupus already. We'll say a little bit more about that as we reveal the results later this year.
Great. Well, looking forward for that update and obviously BROADEN2 as well. But I think we're out of time. Nello and Terence, really appreciate you joining us today.
Thank you. Thank you, Alex.
Have a good one.
See you soon. Bye.