I think we'll get started here with the first fireside of the day. My name's Derek Archila. I'm one of the Wells Fargo biotech analysts. I'm very excited to have Kymera Therapeutics. From the company, we have Nello Mainolfi. Mainolfi, right? Sorry.
Mainolfi.
Mainolfi. It's too early this morning, no coffee.
That's all right.
President and CEO, and also we have Terence Rooney, the new Chief Medical Officer?
Correct.
All right. Got that one. All right. Well, probably one of the most consequential catalysts in small cap biotech this year, coming up for the BROADEN2 trial. Nello, maybe just sketch out for us where you are with your STAT6 program and maybe just a little bit about BROADEN2 before we get into the more specific questions.
Yeah. Thanks for the invite, and great to be here in Boston sometimes. Maybe let's take a step back, just a minute on Kymera for people that don't follow the company closely. We're a company that was founded about 10 years ago with the goal of using and building and evolving and advancing a new drug modality called targeted protein degradation to deliver a whole new generation of medicines. These are small molecule oral drugs that can degrade targets with the efficiency, the specificity that you can see in, for example, oligo-based therapeutics, but with obviously the convenience of oral small molecules. As part of our target selection strategy, we have really focused on pathways with high degree of validation targets that have strong human genetics, but undrugged or poorly drugged.
STAT6, coming back to your question, STAT6 is, we believe, one of the perfect targets for protein degradation. Is a transcription factor traditionally difficult to drug. It's in a pathway that has been extensively validated by multiple agents, but most importantly by dupilumab, which is an IL-4 receptor alpha monoclonal antibody. Again, a pathway and a target that would potentially give the first oral drug in this space. We have generated a plethora of preclinical data demonstrating that targeting STAT6 can block IL-4 and 13 just as effectively as an upstream biologics. We've generated early clinical data that confirmed that KT-621 is a potent, specific, and highly effective STAT6 degrader. Again, a first-in-class degrader.
Also we've shown in a small Phase 1b AD trial that the level of STAT6 degradation lead to a deep the level of degradation that we achieved, which was very robust lead to a very robust impact on type 2 downstream biomarkers, which eventually correlate to meaningful improvements in signs and symptoms of atopic derm, comorbid asthma, comorbid allergic rhinitis. All of this data, all of this 2 minutes or 3 minutes of my talk, has given us the confidence and the excitement to initiate two global Phase 2b studies. One, BROADEN2 that you mentioned. This is a global dose-ranging placebo controlled study in moderate to severe atopic dermatitis patients. Another study is BREATH, which is a global dose-ranging Phase 2b study in eosinophilic, actually I should say, in type 2 asthma patients, so patients with high eosinophils and high FeNO.
I think as you said, and I completely agree, I think it's one of the most exciting programs, our STAT6 program, and namely with the acceleration of enrollment, we have been able to move up the data readout from middle of next year to, as we said, by the end of 2026. That's where we are today. The goal of the study is, number 1, to evaluate the safety and efficacy of KT-621 in a much bigger study, and just as importantly, to select dose for our Phase III program.
Got it. A lot to unpack on the trial. Maybe first, just in terms of your comments there around the enrollment and why it enrolled so much quicker than expected, despite the fact that you were doing a lot in the trial enrollment criteria to mitigate placebo and things like that. Maybe talk about those kind of pushes and pulls and why that's so exciting that the enrollment was so fast.
Yeah. I would start by saying that our projections were based on general execution of any atopic dermatitis studies in this day and age, and also included what we expected the timeline would be in a study that is set up to ensure that quality and speed are equally important, and not speed is the most important parameter. I guess we expected that because of some of the measures that we had put in place to control, let's call it patient quality, that would have impact enrollment. What we've learned that while all those measures that we put in place obviously were not changed alongside the execution of the study, they actually did not impact enrollment. The enrollment went at least as well, if not actually way better than we anticipated.
Mostly, I think because there is a big desire from the AD community to have an oral drug. I think there is a level of comfort that investigators and eventually patients, I assume, have in this pathway, and also the appreciation of the data that we've generated so far.
Gotcha. In a lot of these AD trials, the more contemporary ones, we have seen placebo responses kind of increase, and that presents kind of an execution risk or at least a risk to the trial. Maybe you can walk through some of those quality controls that you were just talking about in terms of the trial that you guys have employed. I guess, again, what you are thinking about in terms of placebo response in this day and age for an atopic dermatitis trial.
Yeah. I think we have seen, I would say more recently, the placebo responses have been generally within, let's say, the historical range. Yes, higher, but not dramatically higher than historical rates. We have had, maybe 2 and a half years ago or so, a couple of really, really bad placebo rates that I think spooked everybody.
I think investors and companies. I think the reflection, if you do a kind of a historical analysis, I think it is true that from the early days of AD development, which I think we should say dupilumab was the first systemic targeted therapy in atopic derm. Let's say from those days, the placebo rates have increased. I think what is a fact is that the severity at baseline of patients that enroll into these studies has generally decreased, the severity. That is mostly because in many of these sites, we all use generally the same sites. These sites have asked patients have access to these advanced therapy, these biologics. Generally, the very, very severe patients are treated with biologics.
In these sites, what you end up seeing are moderate to severe patients, but maybe its severity is less than the first study in atopic derm. So we have seen the mean baseline EASI go from the low 30s into the mid-20s. Again, these are still squarely in the moderate to severe population. But I think with that, you see probably more disease fluctuation as the disease gets less severe. So that probably plays into what we have seen in increased placebo rates. I think another important reason is that because the space is so competitive, I think in some cases, not in all cases, I think you have maybe some poor quality of both how sites and investigators and these studies measure the endpoints or heterogeneity into the measurements because there are many people involved in the studies.
And so I guess just driven by the competitive landscape, maybe some of the quality has been reduced. When you put it all together, what are the things we can control? Obviously, we cannot go and see patients, which I love to do, but we can't. It comes down to ensure that patients on our study have confirmed atopic dermatitis, which, believe it or not, is still something you need to correct for, and we have put measures in place to ensure that the severity is in the, generally, again, the sponsor can get involved into that assessment, but you can put system in place to make sure the severity is in the range that you're studying.
Then, a lot of it, a huge amount of it is site and CRO oversight, which I think we employed as much as we could, a high-touch approach that hopefully will lead to a successful study. Everything I said, I think we've done some of the more creative things that have been done recently. The proof will be in the pudding, so we'll know soon enough.
Got it. I know you've characterized the expectation of having efficacy around dupilumab in the trials that they've produced that data in atopic dermatitis. I guess to you, what's in the range for dupilumab? Does it need to be dupilumab-like, or can it be slightly lower than dupilumab because it's an oral?
Yeah. Maybe I'll take a step back, and then I love to Terence also to provide his view, given that he's been involved in lots of studies with oral drugs and biologics. I'll give you my perspective. First, I think something that we have learned by being in the field of Type 2 inflammation and more in this case, more closely, AD, is that what really patients and prescribers are looking for is an active and safe oral drug. While from a scientific perspective the narrative of oral dupilumab has actually been quite successful one from a both communication and actually the data that we've generated. I think what we have been met extensively is, yes, that would be cool. That would be great. But actually what we need is an active and safe oral.
In a way, what we believe will be an amazingly successful program is a program that has strong activity and good safety. Then maybe we can talk about parallels in psoriasis. Maybe Terence can touch on it. From a technical perspective, I am not going to shy away from commenting on your question. What we have shown to date has been that the mechanistic studies that we have done pre-clinically and everything that we have done clinically, KT-621 seems to be able to block IL-4 and 13 just as well as upstream biologics, and again, namely dupilumab. When I say from a technical expectation, meaning from a scientific expectation, to be in their range is again, I do not know because numbers can be different.
I think when you look at the again, SOLO 1, SOLO 2 data, I think you can see the EASI-75 / IGA 0/1, you can see even across the 2 study, there is a bit of a range. I think in that range that someone would think it is reasonable, is where our expectation lay. Again, from a point of phase III and commercial success, we are not fixated on the dupilumab range. We are fixated on efficacy and safety. Before I say everything, Terence, why do not you share some of your views?
Yeah, look, I just amplify. There is very reasonable grounds to expect scientifically that pathway blockade would be commensurate with the likes of dupilumab, and Nello already told you the story. We have seen that preclinically. We know it from just expected pathway biology, and we have seen evidence of that in the clinic. However, I think we are learning more and more as we speak to patients, providers, and other stakeholders that there is just such an appetite for a safe, effective oral in this space, that precisely having to meet exactly the efficacy bar produced by upstream injectables, not necessarily required. You do not have to look too far around the industry for some examples in the dermatology space.
If you look in an even more mature market, moderate to severe plaque psoriasis. You have seen the recent launch from my old friends and colleagues at Johnson & Johnson of icotrokinra. Targeted oral peptide, selectively blocking the IL-23 receptor. Launch appears to be going extremely well, with a data set that arguably does not precisely meet all of the injectable biologics that came before. On the one hand, we have very reasonable grounds to be optimistic. On the other hand, as you say, I do not think you need necessarily to be at the same bar.
Got it. Makes a lot of sense. I guess, one of the important things that we hear from investors is around, you have three doses in the trial. This is a very potent drug. I think, do we need to see a dose response? I know you're trying to go lower to maybe find a less efficacious dose essentially, which might be a good problem to have, but walk us through that and your expectation.
So just to I think I've said this before, but if not, I'll say here first.
All right.
No, we didn't design the study to deliver a dose response. We designed the study, we believe, to select the best phase III dose. When you think about phase III dose, you want to have the lowest, most active dose possible. I think if you think about the doses that we've selected, I would say probably, let's call it the middle dose, is the dose where we believe we are achieving maximal pharmacology.
Then, as you do if you don't have concerns about safety, which we haven't so far, we ask the question, if you go above that pharmacological dose, do you see more? Do you see the same? Obviously, we don't expect, again, we can be surprised. I wouldn't expect to see a dose response in that, let's say, middle and high dose. Then we select a lower dose where we expect to see less activity. Again, maybe it's not a perfect dose response, but hopefully it's clear that we didn't explore this huge range to demonstrate a dose response. We're really focused on selecting the best phase III dose possible.
Got you. Maybe just to piggyback off the comment on safety. Maybe just walk us through, so far we've seen decent safety, short trial.
Decent? Very good.
Very good. Yeah, very good. Very good safety. Thank you for correcting me. But it's still limited data set.
Yes.
As this will be longer, 16 weeks, what should we think about from just loss of function models? Is there anything that we should be thinking about just in 16 weeks and then going forward to your open label, which is going to go out even longer? I think that's obviously for a chronic therapy. We'd want to see a lot of patient years of data.
Yeah.
What are you trying to amass and what's the strategy there?
Well, high level, maybe it's worth summarizing the safety that we've generated so far. From a preclinical perspective and even looking at human genetics, we know that gain-of-function of STAT6 leads to severe allergic diseases. That is a sign that the target is responsible for Type 2 inflammation and nothing else, at least as looking at those humans. We know the heterozygous loss of function has a completely normal phenotype. From a preclinical perspective, we've run all the tox studies actually needed to initiate a phase III study, including chronic tox. In all of these studies, we have really not seen anything to note. In the clinical space, obviously, as you mentioned, the longest study that we've run before the phase IIb have been 28-day study. Obviously, we've dosed probably close to 200 subjects between healthy volunteer and patients.
We have lots of ends, but short duration.
As we go into these larger studies, obviously our strategy is to amass as much long-term safety data as possible to being able to file an NDA as quickly as possible. The reason for having not only obviously people in 16 weeks, but all of these people are able to join a 52-week open label extension on both the AD and the asthma study, is to, as you say, amass as much safety information as possible. Again, we don't have, besides the pathway events that have been seen in the past, for example, we know that agent in these pathways have generated some imbalance in conjunctivitis between placebo and treatment arm in AD, not in other indications. Besides these that obviously we were curious about and on the lookout for, we don't have other things that we're going into the study expecting or being worried to see.
We're obviously very focused on generating the data, but again, we don't have something that we're trying to de-risk per se.
Should the base case be that we see conjunctivitis in this trial?
Well, I'll share my view, and then I'll let Dr. Rooney share his medical view. My non-medical view is that if I look at this pathway, all the drugs that have targeted this pathway have shown some level of conjunctivitis. I've said this for a couple of years. In a way I expect it, but who knows? We just don't know actually what's driving it. It's hard for me to rationalize one way or the other. Terence.
I would say the asset has behaved well, providing complete and exclusive inhibition of a key node that completely and exclusively serves signaling of the upstream IL-4/IL-13 pathway. We've learned a lot. It's been very well characterized, the safety profile, across a variety of inhibitors of that pathway. Therefore, while we've seen no events to date of things like conjunctivitis, it would not be unreasonable to expect that we would see some as we move along in development. It's a learn and confirm paradigm, and we learn a lot from phase IIb.
Just to be clear, to date refers to the phase Ib.
Got you.
Yeah. In case people want to read into it.
Yeah. Getting a little jumpy.
Yeah.
So, I guess maybe talk about data readout, positive data. You've already operationalized gathering more safety. How fast can you get into phase III? Again, basically walk us through the phase III strategy post-data.
Yeah. Just on the timing, I'll let Terence speak to the strategy. Obviously, we're not sharing details, but to the timing, we've said we should be able. Obviously, there is a regulatory interaction to be had, apparently. But I think we said by middle of next year, we'd like to start our phase III. Terence, maybe you can talk about our strategy.
Yeah. So the phase IIb studies that are running at the minute, that Nello described, of course, are in atopic dermatitis and in moderate severe asthma. Our strategy would be that would unlock a suite of confirmatory studies across the spectrum, potentially, of Type 2 inflammation indications in derm, in resp, and in gastroenterology. Obviously, the first readout will come towards the end of this year, and the readout of the asthma study will come during 2027. We'd be looking to move aggressively across indications from there.
Got you.
Just to add.
Yeah.
It is obvious, AD, because it is moved faster.
It will hopefully be the first indication that we move into phase III, and we plan to move aggressively into that.
When you think about the trials there, I know you guys are talking about going into pediatric and then a formulation there. You already expanded BROADEN2 into adolescence. Again, the number of trials you need to get the full spectrum for AD.
Yeah. The pediatrics opportunity is one we're very keen on for multiple reasons. First, I would say that children are the patient population that I think has the hardest time with injectable. We almost feel, or I shouldn't say almost, but we do feel the responsibility to provide children a convenient option to manage their disease. We had a 5-year-old severe AD patient come and visit us with his parents, and it was clear the struggle that the family goes through even to be treated with existing injectable effective therapy. There is a huge amount need for that population. The pediatrics program is a priority for us. As you said, we have adolescents on the 2B, which we wanted to generate the experience to then make the case to regulatory agencies to accelerate the plan for younger children.
I can't comment on where we are with those plans, because we're still obviously in discussions. Obviously the phase IIb data would be critical. But rest assured that as part of our phase III campaign, obviously moderate to severe adolescents and adult AD patients will always be the first, just because it's a well-established path. But the younger patients are our priority. Now, the timing on when those studies will start, we're not in the position to comment yet. To be fair, our priority for children extends to other diseases, where just the ERS, we had an ad board for pediatric asthma, just again, to think about how to enable that. For example, if you think about EoE, another disease with a huge impact in young children.
Not only we're thinking about plans, but we're operationalizing the right formulation as well in order to being able to support those studies.
Got it. Thinking about AD success, how translatable should that be for asthma?
Terence.
The pathway is well-characterized upstream across both of those indications, including the dose-response relationship across indications for pathway inhibitors upstream of STAT6. We are conducting a dedicated Phase IIb trial in asthma. It would be our hope that when we unlock the BROADEN2 study in atopic dermatitis, as we mentioned a moment ago, that would enable us to move quickly, at least into dermatology indications, beginning with atopic dermatitis. It will give us a lot of information, I think, about what we are likely to expect when we open the envelope on the BREATH Phase IIb study in asthma just a few months later, but that would be the ungating event for the respiratory indications.
To fill in the gap between derm, resp, and GI, eosinophilic esophagitis, for instance, in the middle, we think generally we will learn a lot from the dose response relationship in the first readout in AD to let us make good guesses about where to go in EoE. Generally, strategically, that is the way we would be thinking.
Can you talk through the BREATH trial design and how it differs from some of the other more contemporary asthma trials?
Sure.
Terence, you want to take that?
Yeah, sure. It's a study in patients with moderate to severe asthma. We selected for a group of people with a Type 2 inflammation phenotype. Some people say eosinophilic asthma, but we prefer the term Type 2 inflammation. We've indexed on delta FEV1 as the readout through 12 weeks. It's a more efficient study design for dose ranging. We've got good information again about upstream pathway inhibitors and how delta FEV1 might translate into other longer-term outcome measures. Ultimately, a registration program would be based around exacerbations.
We think we can learn more than enough about through a delta FEV1 efficient week 12 readout in Type 2 inflammation high patients, to make good decisions about Phase III design. Readout will be coming in 2027, and we'll be looking to move swiftly to regulatory interactions from there.
From the original Phase I-B, you shared some FeNO data from those patients. Is that something that you would share potentially for some of the atopic derm patients that might have some asthma symptoms or some asthma acts in there?
Yeah. Maybe a flag. We were the first company to measure FeNO in AD patients. That's a pretty involved operational requirement. We're not measuring FeNO in the BROADEN2 study.
Okay.
Because it will mean that all these AD sites will have to have a FeNO machine, which is basically impossible. There are other measures of asthma comorbidities and others that we're capturing. I don't believe they will be shared in the top line.
But eventually we'll make sure we'll share. As Terence was saying, those are things that we will learn that will obviously, we believe, continue to de-risk the asthma program.
Got you. Then, so you were kind of hinting at this, Terence, but in terms of after proof of concept in AD, proof of concept in asthma, the regulatory strategy post that is just to start Phase III trials.
Yeah.
And really accelerate development. I guess we got a playbook from Dupil, which ones do you feel like are the ones that, I guess, are priority for you and ultimately are probably the most de-risked from the two trials that you guys are currently running?
I think we look at that. So obviously there are, I think now nine indications in which dupilumab has been approved in. If you look at probably the first four or five, still account for 90%-plus of dupilumab revenues. So if you look at AD, asthma, CRSwNP, EoE, and probably eventually COPD, that's probably close to almost 95%-plus. I would say those are the kind of indications we're thinking about. T he sequence, again, some of those obviously we're still refining time, et cetera. But as Terence said, the sequence is AD will allow us to go into all the other derm indications, ideally directly into a registrational study. We believe EoE can be informed enough so that we can move swiftly through a potentially creative registrational study. We'll talk more about that maybe early next year, definitely after the BROADEN2 data.
Then as soon as we unlock asthma, we have asthma CRSwNP, and potentially COPD that can be unlocked. W e're trying to actually do as much in parallel as possible, but we have these gating factors, which are the phase IIb data and the phase III dose. Because while I think it's fair to assume that the phase III dose for AD is the same as the phase III dose for asthma, we're going to have to make that as a data-driven decision.
If we have different doses, obviously will require different kind of approaches for these derm versus respiratory diseases.
Got you. Maybe with the next 5 minutes, we could talk about KT-579. Another program, IRF5. Why do you like this program? Why this target? In terms of your kind of vision to be a powerhouse in I&I, what does this unlock for you?
Yeah. Maybe I'll touch a little bit on it, and then I'll let Terence speak to the program per se. First, remember this is going to be our next dataset. We've said that the IRF5 phase I data will be before the BROADEN2 data.
That will be on the lookout for that. The beauty of this target is the fact that, again, it's another transcription factor, undrugged, highly pursued by the industry, with strong human genetics, and with opportunities across multiple indications. I think while, if I can complain a little bit, while it's, I think, completely underappreciated, I think it's one of the most innovative programs in the industry and immunology right now. Maybe Terence can speak to the biology and clinical opportunities of it.
It is a node that sits downstream of a number of validated pathways. I should say upstream in some ways, upstream and downstream. It has strong genetic validation in a variety of rheumatic diseases and in gastroenterology. That includes lupus, rheumatoid arthritis, Sjögren's disease, and inflammatory bowel disease. If you look at where it sits in pathway biology, it is downstream of a variety of pattern recognition receptors and upstream of at least three pathway areas that have been clinically validated.
That includes type I interferon signaling, a variety of cytokines, including TNF-alpha and the IL-12/23 cytokines, as well as IL6, and then finally, B-cell biology, including autoantibody production. You can imagine the penumbra of indications that might potentially touch. In development, we are, as Nello flagged, planning to graduate from phase I this year and intend to reveal those data before the end of the year. What we have expected to see from data generated in the past, aligning with what we have seen with our previous clinical degrader, is fairly complete degradation greater than 90% of the target, inhibition of downstream pathway relevant cytokines, which we generate in phase I in healthy volunteers, and we have guided to seeing and to expected to see somewhere 80% plus inhibition of those downstream cytokines, and obviously a well-characterized dose PK and safety profile from phase I.
All being well with that, we would look to proceed to show proof of mechanism, proof of biology, and maybe some proof of concept in a relevant disease. I have mentioned some of the diseases earlier on that might be in scope, so look forward to announcing that soon. I would amplify what Nello said. I think there is tremendous opportunity there. First-in-class molecule and a great target to select for a degrader.
Got you. Then maybe just the last question, the high level question for Nello. Obviously, as I said, very consequential year for you guys, and I think the industry as a whole, in going into the BROADEN2 readout. Kind of taking it all together in terms of what the platform's ability to do with STAT6, IRF5, and other targets that you guys have pursued, where do you want to go with this? What is next in terms of other opportunities in disease sets within an I and I?
First I would say thanks for the question. We want to build a commercial global biopharma company that can do innovation and deliver what patients are looking for, which are effective oral drugs. That is our mission. We feel the responsibility. We are, I think, well set up for it financially, and we now have to execute and generate great data. I think STAT6, I believe, and I think this is probably shared by many people in the industry, is one of the most exciting targets and potentially one of the most compelling medicines in Type 2 inflammation. IRF5, I think, can open up completely new opportunities for patients that suffer from these diseases that Terence was talking about. Again, an area that we have often discussed is, I think another pillar of immunology, which are diseases driven by autoantibodies. I know you keep talking about a target.
You might be right or wrong, but that area is an area that we're very keen on, and we continue to do work on, and hopefully soon enough we'll be able to talk about it. We are very keenly looking at how do we allow patients to continue to be treated in the most effective way. What is the right synergistic biology for either having deeper responses or broader responses in this heterogeneous patient population? Combination therapies, oral combination therapies, which I don't know that anybody is doing right now. We're seeing a lot of bispecific and trispecific. I think that's another frontier that we're going to be exploring in the next few years, and we have lots of novel targets that we're working on and hopefully be able to disclose in the next few months and years.
Excellent. Well, Nello, Terence, thank you so much for joining us. Really appreciate it.
Thank you. A pleasure.
Thanks for having us.
Thanks so much.