Welcome to the second day of the Citi BioPharma Back to School Conference. I'm Geoff Meacham . My team's here with me as well. I'm the Senior Biopharma Analyst. Our next session is Kymera Therapeutics. We're thrilled to have CEO Nello Mainolfi, President and CEO, sorry, and then Jared Gollob, CMO, Justine from the IR team. Bruce may or may not be here. Maybe Nello, thanks for joining us, by the way.
Thanks for the invite.
So a little closer than Napa, but maybe not as.
Yeah. Well, finally in Boston. Thank you for doing this.
Exactly. We did it just for you.
Thank you.
So let's, I guess, talk about the platform. So for TPD, it's been a hot area for quite a while. There've been some companies that have had some success, more differentiation than others. You guys have had a lot of success with respect to a couple of assets moving forward, good partnerships. Maybe talk a little bit about how your platform has kind of evolved since you've started Kymera and maybe what types of attributes you're looking for for assets to come out versus when you, again, when you first started.
Yeah. No, this is a great question. Again, thanks for the invite. So we started the company nine years ago, so next year will be 10 years, with the goal of building a whole new category of medicines using targeted protein degradation. And the idea has always been marrying the best of what the technology can do with an unmet need, an undrugged protein, a problem. So it's really solving a problem with protein degradation. And so that's been always front and center for our target selection. So we usually like to focus on these key pillars of we like to work in pathways that have been validated already, targets that have never been drugged before, having an ability to kind of prove the concept early in clinical development and accessing ideally millions of patients and not thousands of patients.
What we've decided in the past, really five years, was to focus almost completely in immunology. The reason is quite simple. Immunology has validated many pathways with upstream biologics, but has very, very few highly effective, safe oral drugs. The reason, the more simple reason is that traditional small molecule inhibitors have a really hard time blocking the pathway as effectively as biologics. So thanks to the platform, thanks to the power of protein degradation, we can catalytically remove disease-causing protein and block this pathway completely. This allows us to have oral drugs with biologics-like activity. That's, I think, a very new concept in drug development, a concept that we believe we're at the forefront with. If you look at our pipeline with STAT6 and IRF5 and even programs that we partner like IRAK4, I think, are a testament to this strategy.
The only other thing I want to add to this is our platform has evolved over the years. Our capabilities have evolved over the years. What we're able to do today, honestly, we were not able to do nine years ago, eight years ago, or even seven years ago. The capabilities we built are about finding small molecules that bind to undruggable proteins in a highly specific manner, designing highly active equimolar, orally available degraders, and translating this into the clinic with a high level of fidelity. I call our new program, our second-generation degraders like KT-621 and KT-579, our STAT6 and IRF5 programs very different than early program, than 474 with IRAK4 or some of the early oncology programs because we have evolved and learned on how to do this better and better. That's, I think, what makes us a very unique company in the space.
Look, I guess last platform question before we get into the pipeline. Has the body of knowledge on the degradation pathways afforded you meaningfully more opportunities? Have you guys deployed things like AI, machine learning to kind of open up new avenues of the pathways? Essentially, it's about the universe of druggable targets, right?
Yeah. No, that's another great question. So I like to think about kind of we have different problems and different opportunities. Maybe the most foundational one is what are the target types or the actual target that the technology can be deployed against, which, as we've always said, we like to go after targets that have not been drugged or drugged fully in pathways that have been validated. So there are nowadays very, very high-end natural language models that allow you to identify targets with specific features. And so using large data set to identify these targets. Then the kind of the next problem is how do we find these small molecules?
In the hit finding and the hit evolution, there is obviously opportunity for machine learning algorithms to identify both the type of scaffolds that will interact the best with the protein class and then understanding specificity and druggability. As we think about translation, what are the biomarkers that we should follow? We look at, again, large data set to understand what's been discovered already versus what we can innovate with. Again, I think the point is you need to continue to innovate to be at the front edge of drug development. I think in this day and age, if you don't innovate, even if you're starting the company with a new modality, you will soon become reproducible. That's not from others. That's not what we want to be.
Okay. Makes sense. So for 621, you're transitioning from phase I to phase II in atopic derm. Give us some maybe context for what are the considerations as you move? Is there a biomarker kind of threshold of efficacy you're looking for? Give us some perspective on maybe the potential for higher doses, higher efficacy. How do you think about that in the context of maybe maximizing your phase II- B effect size?
Yeah. So 621 is a first-in-class STAT6 degrader. Just a quick review of the target. STAT6 is the specific transcription factor of IL-4 and IL-13. And blocking STAT6 with our technology is really the only way to phenocopy the blockade of both IL-4 and IL-13. Why is it important to block IL-4 and IL-13? Because only by blocking both cytokines, we're able to block all type of Th2 inflammation. Unlike if you block IL-13 only, you will only be efficacious in a subset of Th2 diseases. So with an oral once-a-day drug, we can block IL-4 and IL-13 as well as an upstream biologics like dupilumab. We've shown in preclinical studies that, again, by degrading STAT6 90% or more, we can phenocopy dupilumab in a plethora of preclinical studies. In the phase one, we've shown that degrading STAT6 at very low doses, we can degrade it fully.
This is not only well tolerated, but it blocks Th2 cytokines in healthy volunteers as effectively as upstream biologics. Now we're in a phase I-B study in moderate to severe atopic dermatitis patients where actually our goal is not only to demonstrate that we can translate this amazing degradation profile from healthy volunteers to patients, but that that type of profile results into biologics-like biomarker as well as clinical endpoint effects. Now going back to your question, Jeff, sorry for the long answer here. I can't wait until we initiate our phase II studies because it is, I think, one of the most exciting studies, if not the most exciting study we've run at Kymera. We'll have two parallel studies, one in AD that we're starting in the fourth quarter and one in asthma that we're starting in the first quarter of 2026.
These are four arms, so three doses plus one placebo, double-blind placebo-controlled study. The goal is really being able to demonstrate in a dose-ranging manner what is the level of degradation correlating to in terms of effect size. So our goal in the dose ranging is to have a range that will allow us to ask important biological clinical questions. For example, what is the effect of maximal degradation of STAT6 in AD and in asthma? What is the effect of less than maximal degradation of STAT6 in AD and asthma? And what is the effect of less than less? I don't want to say percentages degradation of STAT6 in AD and asthma. I believe being able for the first time in drug development demonstrate what is the exposure and degradation profile that is required to have maximal benefit in patients.
That's, I think, a very exciting place to be.
You feel pretty comfortable on the healthy volunteer study that you can get to precise points in terms of STAT6 degradation. You feel like you can get to almost 100%.
Yeah.
Based on your doses.
Yeah, that's a great question. So I think what we've demonstrated in the healthy volunteer study is that any doses above 1.5mg once a day, think about that, above 1.5mg once a day, we're able to degrade the target at 90% or more. So the way I think about it, I think about buckets of doses. There is the doses that went from 50mg- 200mg that completely removed STAT6 in blood and skin. There are doses that go from 6.25 mg- 25mg that degraded STAT6 between 90% and 95%. And then doses below 6.25mg that degraded less than 90%. So that's how we think about it. It's not really one discrete dose that gives us exactly that 90%, but we have small ranges of doses that capture a degradation profile.
Those are the principles that we're thinking about using as we move into phase II-B studies.
Yeah. And then your upcoming phase II-B data, it's going to be later this year. The STAT6 degradation levels in AD patients, they differ versus healthy volunteers. So how do those levels kind of impact the efficacy levels? And considering the baseline levels are higher in AD patients, how do you think those could impact the efficacy data that could come in phase II-B?
Yeah, I'll let Jared take this one.
Yeah. I mean, what we know about STAT6 levels in healthy versus AD patients, we know in the blood, the levels are actually similar. In the skin, it looks as though there might be a two- to three-fold higher level of expression in active AD skin lesions compared to healthy volunteers. Overall, that delta is very little, especially for a very potent degrader like 621. We're not expecting that we have to overcome higher levels or that we have any problems matching degradation. Of course, that's the whole one of the main points of the phase I-B is to show, hopefully, that we have high fidelity of translation from the healthies to these patients, both in blood. Our hope is that we'll see comparable levels of degradation in blood, comparable levels of degradation even in active skin lesions.
That will be a very important part of the translation, and then showing, of course, comparable safety, and then, as Nello was saying earlier, the next level is to show that we can have a Dupy-like effect on Th2 biomarkers, and we have an array of biomarkers that we can look at in patients. Whereas in healthies, you're talking about looking at biomarkers like TARC and Eotaxin-3, which are expressed at low levels. Now, in patients, especially biomarkers like TARC in AD patients, we know in AD patients on Dupy studies are expressed at very high levels, and so we have more of an opportunity now to show, hopefully, a Dupy-like effect, even with 28 days of dosing, which is the duration of dosing in the phase I- B.
And also an opportunity to look at skin biopsies in the AD patients and to look at skin Th2 transcriptomics and to hopefully also show a Dupy-like effect on those Th2 genes and their expression in skin where we can sort of look at a high level at whether we're in that same sort of ballpark of what we would expect to see from our drug based on what Dupy is seen both in the skin and in the blood.
Let me just add one quick thing. If you look at the healthy volunteer data, let's say in the skin, which is I always think it's a higher bar than blood, we have seen intra-patient or intra-subject that you've seen levels of STAT6 levels at baseline that could be even in healthy volunteer, two- to three-fold versus one versus the other. And even with those differences, we've seen consistent degradation. So that's why we're going into the study in patients with that confidence that this drug is very potent and very catalytic and the starting point of STAT6 should not have an effect.
Then at the recent call, you also mentioned that you added an extra dose, extra arm in the phase I-B study. Do you think for that, I mean, I know you haven't given particular dose levels, but do you think it's more appropriate to add a lower dose considering you have seen a really broad efficacy in the healthy volunteer data? And if you see an effect with a lower dose, that could help you with selecting those levels in the phase II-B?
Yeah. I mean, without getting into the lower or higher, which I don't think it makes sense at this point to get into it. But what I can say is these phase II-B studies are, as I said earlier, the most exciting, but also the most consequential studies that we've run at Kymera to date. And we were very fortunate that our phase I healthy volunteer study was so robust, as I think was agreed by everybody, that we were able to make an initial decision on the phase II-B doses. So what we wanted to use the phase I-B study for, again, not only, as Jared pointed out, understanding the cytokine and efficacy profile, but also to see how do we translate into patients? And importantly, how do we de-risk the phase II-B dose selection? How do we confirm it? How do we refine it?
Obviously, we started with one dose. The idea was if we're able to actually get another dose in within the same timeline, we'll be able to have much more confidence in the phase II-B dose selection. It was purely based on making sure we have enough data points to be absolutely certain about the phase II-B dose selection. We were fortunate enough that we were able to do that so quickly that we didn't even have to wait for the end of the study to make the final phase II-B dose selection, which I will say has been consistent from the early days to today. Nothing that we've seen in this study has informed that we were expecting anything different than what we had initially thought.
Maybe just to quickly add that sometimes we get the question, well, did you add another dose because you saw a safety issue? And we did not. So essentially, that did not factor into our thinking. It was more around what Nello was saying and wanting to have a richer data set to confirm phase II-B dose selection.
Just a quick follow-up. I guess, is there a correlation between when you intervene and STAT or any degrader, for that matter, and when you see a clinical effect? I guess I'm trying to figure out you have the potential for a pretty rapid onset of action. Is that something to expect? Or is there sort of a delayed just given the pathway and the mechanism, is there likely to be a cumulative delayed effect and then you see a clinical effect?
Yeah. So I think what is fair to expect is that we'll have a very rapid onset of degradation. We know that for the right dose at four hours already, which probably means that at two hours, most likely, we already have maximum degradation. So we can ensure that we have very rapid degradation. Then the question to onset of clinical effect really comes down to either onset of pharmacological intervention or onset of kind of how the biology plays out. And that's actually an interesting question for our phase I-B study, which will be very focused on the first four weeks. Is the onset of effect of dupilumab? Just remember, dupilumab gives a loading dose at day zero, right? So these patients get full blockade of the pathway right away. And then obviously, they get another dose after two weeks.
Is the rate of effect of dupilumab driven by the biology? And if it's a biological question, then you'd expect that STAT6 rate of response would be similar. If it's an onset of pharmacological intervention, meaning degrader moves faster than an antibody to reach all the receptors, then you might see a difference. I think that's an important question for our phase I-B study and more importantly for the phase II-B.
Then for phase I-B , of course, you're running both the arms as drug and there is no placebo arm. In terms of data, what sort of data you'll provide EASI, pruritus and then biomarkers that could help investors frame the data and compare to biologics?
Yeah. I think some of you have followed us for many, many years. We tend to overshare than undershare. So you will get the totality of the relevant data, the degradation profile in blood and skin, the biomarkers in blood and skin, and the efficacy endpoints that are the ones that are obviously measured in any AD study. So yeah, we will share all of that as we've done consistently in the past few years.
Moving to the phase II-B kind of patient selection and stratification. In terms of patient selection for moderate to severe disease, would you be using some biomarker stratification to select patients, like some EASI levels or any of those kind of metrics to select your patients for the phase II-B study? Considering there has been some data that EASI 16 level and higher patients are kind of more responsive to this kind of treatments.
Yeah. I mean, it's a good question. I mean, our approach to phase II-B eligibility will be similar to phase I-B to try to select for moderate to severe. So as you mentioned, the standard metrics that you use for inclusion and exclusion are usually things like EASI, vIGA, BSA, for example, all of those things at baseline pruritus. Because you want to really make sure, number one, that you have bona fide AD patients, and you want to really make sure that you truly have moderate to severe AD patients. So all of those, we're planning to use all those. We're not planning on using sort of unorthodox plasma biomarkers to somehow establish cutoffs for eligibility.
But I think for the standard sorts of eligibility criteria that you've seen for other studies, whether it be with Dupy or Lebri or others, whether it be phase II, phase III, those will be similar to ensure that we get the moderate to severe patients.
Along those lines, is there a way to, I know in clinical development, you can add novel biomarkers, but are there any that you'd want to elevate to maybe being more clinically meaningful in the eyes of the FDA? In other words, can you in these studies also engineer an atopic derm or whatever the indication, a newer biomarker that's maybe Kymera specific that could help you commercially?
I mean, I would start with kind of the purpose of inclusion and then the purpose of monitoring effect, so for the inclusion, we want to make sure that we are using criteria that have been used successfully to treat moderate to severe patients by successful drugs. And so our bar is going to be very high as it's been for successful drugs, so EASI 16 and above, etc. I think one other thing I would add is while we won't use them as criteria, we are watching other biomarkers of Th2 inflammation at baseline. You can think about eosinophils. We look at IgE. We look at other biomarkers just to make sure that we're really interrogating AD patients with Th2 inflammation. With regards to biomarkers that we will generate, we are continuing to advance the science of STAT6, so let's not forget STAT6 is a novel target.
KT-621 is the first agent ever to target STAT6 in humans. We are doing work in the phase I-B study to understand the profile in blood and skin of a STAT6 agent. We will continue to explore clinically these areas. Should new opportunities arise from that, obviously, we'll take advantage of it.
Yeah, and for phase II-B, at least the injectables, the data that in AD have been seen recently that you have a lot of placebo responses are variable across the trials and such variability. So in terms of your site selection and other strategies, what are you employing in phase II-B? And whether you think as an oral drug, you probably won't see as much variability? Or are there any kind of information you can provide along that, considering yours is oral and those are injectables?
Yeah. I think your question around what would we or any company do in the AD space to try to minimize placebo effect because that's obviously important, and there are a number of different things we can do. It all begins, I think, with the protocol itself, right, to make sure the protocol has the correct eligibility criteria and the correct MD oversight of screening and determination of eligibility from the different sites. So we at Kymera play a very active role, not just in phase I-B, but in phase II-B, in making sure that the patients who are being selected and screened are the right patients who truly meet the letter of what's in the protocol with regard to eligibility.
Along those same lines, it's really important that we choose sites that have a very good track record, right, in the AD space, sites that have investigators, preferably investigators who have done this sort of rating before for AD and are experienced at it. So we know that the sites are going to comply with the protocol and do the rating as we want it to. So we're very careful with regard to site selection, and again, very rigorous when it comes to oversight of these sites, not just relying on a CRO for oversight, but Kymera oversight of what's going on.
So I think those are among the most important things that we can do to try to minimize placebo effect, also making sure that patients are not taking other medications that they're not supposed to take according to the protocol and that they're being compliant, taking the drug on protocol. All of those things, we're all over to really make sure we can do all we can to minimize placebo effect.
I want to put the cart before the horse and ask you about commercial strategy. But when you look at atopic derm, are there patients today that are maybe underserved or unmet with some of the many therapies that you can correlate maybe STAT6 to or breakthrough or something like that? I wasn't sure if there's a lot of science behind non-responsive patients or refractory patients.
Yeah. I mean, the beauty and actually also the sad part of it is that we don't even have to do that. The reality is that there are 100 million patients with Th2 diseases. There are tens of millions of patients in the U.S., which is the country in the world that has the highest biologics penetration. And even with the highest biologics penetration, just in AD, dupilumab has less than 15%, I believe. And this is in the so-called biologics eligible patients. If you look at all the moderate to severe patients, the penetration is, in our calculations, less than 5%. So actually, we don't have an issue with having effective drugs that work for a lot of patients. We have an issue with access, reimbursement, and eligibility.
So if you have an oral drug that is well tolerated and is quite active, we believe it should be the first-line drug for all Th2 patients. We're talking about millions of patients. And I would say, actually, the worst part of the current system is that there are many adolescents as well as young children that, unfortunately, either for access or, more importantly, for inconvenience, are not treated with very severe Th2 diseases. So we believe this is going to be a game changer for adults and children.
Okay. Makes sense.
And one on your STAT6 kind of differentiation. Of course, you are the one who has actually shown data in healthy volunteers. And there are a lot of other companies which are kind of behind you. So in terms of differentiation, do you think the timing is only the differentiation, or do you think your platform or just your molecule is much better in terms of structure and everything?
I think you had the answer in your question. You said we're the only company that has shared data. I don't have to differentiate if I've shown the data. I think it's the other companies that need to come up with a reason why they should develop a STAT6 agent. Now, it'd be too easy of an answer for me if I just stop there and probably not nice to you guys. I will give you also the other part of the answer, which is, so yes, I think KT-621 is, in my experience, one of the best-behaved molecules I've ever seen in my career. It's extremely potent. It's actually intrinsically more potent than dupilumab at blocking IL-4 and IL-13. It's highly bioavailable in humans. It degrades the target and 90% plus at doses of 6 mg once a day and above.
In preclinical species, in efficacy models, it looks equal, if not superior to dupilumab. In the phase one study, even in biomarkers, it's at least numerically similar, if not superior. So the question that you have to ask yourself, what are these competitors trying to do? Obviously, until KT-621 is approved, there is always an opportunity for others to compete with us. We have a multi-year gap right now in terms of being in front. Our goal is to increase on that. Again, we have a second-generation degrader that we've now, let's say, parked in IND ready, which is more advanced than any other competitor in the space. So it just tells you the level of investment in the chemistry and the advances that we've made. So we're not obviously sitting on this and basking in our success.
We're focused on getting to registration ASAP with the best drug possible. And I would, I guess, ask others, how are they going to try and differentiate and if they can catch up?
With that same, I guess, related question on IRAK4, so there is a broader body of work on that. Not to get too much in the weeds of the competitors, but where do you see the most points of potential clinical differentiation for your asset?
Yeah.
I know Sanofi is obviously running the.
Yeah. So thanks, Geoff, for asking these questions. Obviously, you've followed us for many years, so you know us well. This is a point of pride that whenever Kymera started the program, there have been multiple companies following. That happened with IRAK4. We've had companies like Gilead and Nurix. We've had Biogen. We've had others following our footsteps. With STAT6, obviously, exactly the same has happened, similar sets of companies. So it just tells you that when we select a target and we deploy our technology, we can create some very compelling profiles. So with IRAK4, as you all know, KT-474 is kind of concluding the existing phase II studies. We're kind of wrapping up where patients were being dosed. And then Sanofi decided to focus on the second-generation degrader, which is KT-485.
The reason for that decision was that KT-485 has a superior, materially superior profile than KT-474 and potentially best-in-class profile, and Sanofi is going to start the phase I study in 2026 from what we understand. I haven't seen data from other companies, again, so it's difficult to compare. What we have done with KT-485 is to develop a drug that is more potent as much deeper skin distribution and degradation and is completely void of that subclinical QTc finding that we saw with KT-474, so it's set up to potentially be best in this category. But I think we'll have to wait for clinical data to be the judge of that, given that now we and other competitors are roughly around the same kind of stage of development.
From a mechanism standpoint, do you think IRAK4 versus STAT6 has the applicability across different disease areas similar or?
Yeah. Great question. I think if you are smart at developing these two assets, you would use STAT6 for all Th2 diseases as we are, and you will develop IRAK4 for IL-1, TLR, Th1, Th17-driven diseases like HS, asthma, COPD. You can even think lupus, IBD. I think there is very little overlap between these two drugs if you're pretty clever about how you develop them.
When you think about the, as you scale up from both programs from phase II to phase III down the road, is there any nuance with respect to manufacturing capability or unique attributes that you'd have to invest in today?
That's a great question. So these are small molecule chemistry. While they're slightly bigger, they do not require any different strategies or even cost. Cost is not materially different than traditional small molecule. It might be slightly elevated, but not materially. And so we, I mean, obviously, we have a great CMC team that is focused on making sure we have the lower, the highest quality and the lowest cost of goods for increasing margins on our drug. And we're well on track for the drugs that we're in full control, like KT-621. We're already planning our phase three manufacturing and commercial at this stage just because we believe that we want to move to market ASAP.
I know you guys are obviously squarely in the oral development stage. Do you guys have an active dialogue with the administration on this pill penalty? I kind of hear back and forth, but it feels like beginning of the year it was very likely to be removed. It just depends on the day, it seems like, in terms of its priority.
Great question. I think so we've been, we as a biotech, let's call it biotech ecosystem through trade organizations, we've been in touch with the administration, but in general, I would say, Congress to figure out a way to solve something that I think was not well thought out, which is changing, having different treatment for small molecule nine years versus biologic 13 years, which obviously makes no sense. Small molecules are just as innovative as biologics, if not more, if you look at what we're doing and should be protected to continue to invest in innovation. I think this is one of those things that it's highly technical, requires somebody or a group of people that are willing to go and solve a highly technical, but at the same time, very simple issue, and I think we're continuing to advocate for it.
I'm highly confident that we will be able to solve this because it's a very simple correction, but changing pre-existing regulation, as you know well, there is such a high energy barrier to it that requires a lot of work.
Yeah, for sure. And then last question on IRF5, the next-gen sort of degrader, maybe just put that mechanism, that in context with IRAK4 and STAT6.
Yeah. So obviously, STAT6 is the best. I'll call it the best Th2 target. And IRAK4, it's more traditional IL-1, IL-17 biology, TLR, IL-1 family. So with IRF5, we have one of the few cases of highly credentialed, genetically validated target that has been associated with lupus, IBD, RA. And there are very few cases, if you look at drug development, of this strong of a genetic association, very few cases. And all those cases have been successful mechanisms. So that's why the whole industry is very keen on IRF5 as a mechanism. It's extremely technically difficult drug to target to drug. And so we've done, the team has done an amazing job identifying highly potent and selective molecules. The opportunity here is to block inflammation only where it matters. So some subset of cells, B cells, NK cells, macrophages, only in the disease state.
That's very few mechanisms that can afford that. IRF5 is one of them.
Perfect. Well, thanks a lot for the time. Yeah, Nello, Jared, yeah, appreciate it.
Thank you.
Great conversation.
Thank you so much.