Back on Alex Thompson's bicycle, and I'm with Stifel . Very happy to have Nello Mainolfi here, CEO of Kymera Therapeutics. Maybe I'll kick things over to Nello to start off with a brief overview of Kymera, and then we'll get into a Q&A.
Thanks, Alex. Thanks for having us. I'll try and keep it brief on Kymera as an overall story. You know, just to remind everybody, we founded Kymera about nine and a half years ago with the vision of developing a whole new generation of medicines using targeted protein degradation. This modality allows you to use a small amount of drug for a short amount of time, thanks to the catalytic mechanism, to remove completely disease-causing proteins. We have focused, in the past, I would say, five, six years, mostly, if not only, in immunology. We have a very, I think, unique insight that in these highly validated pathways, especially by upstream biologics, if you identify the right target, you can use these catalytic mechanisms to remove completely the protein and block the pathway as effectively as an upstream biologic.
You can have, for the first time, reliably, oral drugs with biologics-like activity. The type of targets that we like to go after are the ones that have not been drugged before. Naturally, that's what the unmet need is and where the technology marries the unmet need. Mostly you'll find us focusing on transcription factors like STAT6, IRF5, multifunctional proteins like IRAK4, and other proteins that you'll see emerging from our pipeline. Where we are today, we have the first in the clinic STAT6 agent, KT-621, and STAT6 degrader. We've demonstrated preclinically that by degrading STAT6, you can reach dupi-like, dupilumab-like pathway blockade of IL-4 and IL-13. We've shown that you can affect downstream biomarkers as well as upstream biologics.
We've shown with phase I clinical data we can degrade the target fully and safely and block type 2 biomarkers as effectively as upstream biologics. KT-621, our STAT6 degrader, has the potential to be the first type 2 oral drug in the space that can serve, you know, north of 100 million patients around the world. Very excited about the program. We just completed phase IB in atopic dermatitis with data in December. We also have started a phase IIB study in atopic dermatitis recently, and we plan to start the phase IIB study in asthma in Q1 of 2026. We have an IRF5 program.
This is another undrugged transcription factor in the type one interferon, B cell, as well as the traditional, let's say, IL-6, IL-23 cytokines that, we have a first-in-class degrader for, that will go into, in the clinic early next year, with data in 2026. We have several exciting programs that we plan to disclose, hopefully at least one next year, still in immunology, going after undrugged targets or poorly drugged targets, with oral drugs. We have two partner programs, an IRAK4 degrader with Sanofi. We have a second-generation molecule starting phase 1 next year. We have a partnership with Gilead on a molecular glucidic A2 degrader that we hope to transition to Gilead next year.
Great. A lot going on.
Only, only three minutes.
Yeah, only, only three. That was pretty good. That's pretty good. Maybe I'll start with, obviously, 621 and STAT6. You know, I guess in the context of your platform, thinking about, you know, targets for degradation, what makes STAT6 such a compelling target for you and your platform?
Yeah, you know, when we, a few years ago, we looked at what are the most well-validated pathways in immunology that lack a, that have a, a mega blockbuster upstream, biologics, but lack a, an oral solution to it. And IL-4 and 13, dupilumab, you know, is, is likely going to be a $30 billion drug, by the end of this decade, is by far the, probably the most successful drug right now in immunology and blocks the IL-4 receptor alpha, that blocks IL-4 and 13 signaling. We had this unique, again, insight that there is a transcription factor that is highly specific for IL-4 receptor alpha, which is STAT6. It actually binds to the IL-4 receptor alpha when, when the, the receptor is activated and then translates the signal to the nucleus.
This is a traditionally very difficult to drug transcription factor that, we only need to find a neutral binder to, to then affect degradation. We know that in immunology, once-a-day oral drugs are the holy grail of therapeutic intervention, and we believe that only with a degrader you can deliver that type of profile.
Yeah, I guess can you maybe elaborate a little bit on that? If you look at the STAT6 landscape, you know, you're in the lead. There's other degraders out there. There's also small molecule inhibitors. What makes this uniquely challenging of a target for a small molecule inhibitor?
Yeah, so, you know, the transcription factor, STAT6, it does basically three things. Binds to the receptor, gets phosphorylated and then goes into the nucleus, binds to DNA, and affects transcription. These transcription factors are not evolved to be blocked by small molecule inhibitors. You can block them in the SH2 domain, which is a highly polar pocket where you have often challenges with molecular properties, or, you know, you can find other ways to block the function of this protein. Obviously, more recently we've had, including Kymera, we haven't disclosed that, but we've had efforts where you can use small molecules to inhibit the function of this particular transcription factor.
The reason why we've prioritized degrader, not just because we're a degrader expert company, but also because of the expression of the target, and we believe the necessity to block this target completely or almost completely, with a small molecule occupancy-based technology, you need exceptionally high exposure of drug for 24 hours, which we believe for a target like STAT6 is impossible to achieve with once-a-day oral drug.
Yep.
While with a catalytic degrader, we actually only need a limited exposure to remove the target completely. I do not, I am not saying that small molecule inhibitors will not be efficacious. What we are saying is, in order to have complete blockade, which, as we know, biologics can have.
Yep.
and a complete blockade that degraders can achieve, you know, it's not gonna be able, it's not gonna be achievable with a small molecule inhibitor.
Yep. And so you alluded to the phase one healthy volunteer data you had earlier this year. You know, what were the key questions that you really wanted to answer coming out of that dataset? And, you know, what are your conclusions?
Yeah, so if we go back to our preclinical data, what we showed, if you degrade STAT6 90% +, you can block the pathway just like an upstream biologics, and you can measure it in human cells in preclinical models where we can show impacts on biomarkers or also on disease endpoint, like in the asthma study where we ran head-to-head to dupilumab. We show that, again, if you degrade 90% or more, you can impact TH2 biology as well as an upstream biologics. Preclinically, we've shown that the drug was very well tolerated, so much so that in every tox studies that we run, we did not see any adverse event. For us, being able to demonstrate in healthy volunteers that we can degrade the target 90% + safely and impact downstream biomarker was our goal.
It turned out that we were able to degrade the target fully at doses of 50 milligrams and above in both blood and skin. We were able to do it very safely. We had a placebo-like safety profile.
Mm-hmm.
Even though the biomarkers in healthy volunteers are noisy because they are not able to elevate their baseline, we were able to show both on TARC, eotaxin, that we were able to modulate them, at least as well as upstream biologics. Basically saying that we can degrade STAT6 safely and degradation of STAT6 has a functional effect on the pathway.
Yep.
That seems to be equal, if not numerically superior to, drugs like dupilumab.
You know, coming out of this study, you also have a phase I-B that's going on right now. You've stated in the past that you really didn't need this study. You know, you have the phase I data, that would be sufficient for you to move into a dose ranging study in atopic derm patients, a 16-week study. Why run that phase I-B ?
Yeah, so you're right. I'm not gonna repeat what you said. We could, and companies have gone from healthy volunteer studies into phase II-B dose ranging studies. Obviously, we believe we had the phase II-B study was the study on critical path. The focus at Kymera has always been, we need to start the phase II-B study as soon as possible. We realized we had a small window of opportunity where we could do two things, generate data to support and validate our phase II-B dose selection.
Mm-hmm.
Generate early proof of concept data that will serve us in two aspects. The main one, generate more reasons to believe and excitement in the medical and patient community.
Mm-hmm.
To enroll our studies in a timely manner and also give us and our shareholders, you know, a complete translation.
Mm-hmm.
We've translated from preclinical to healthy volunteers. But, you know, the real translation is, can you degrade the pathway, the target, and affect the pathway biology in the relevant patient population?
Yep.
Whilst it is true that a small study without placebo will always incur in, you know, potential noise and potential, you know, challenges in interpreting all the endpoints in the study.
Yep.
We've always had the confidence that the drug will be able to deliver a dataset that would be both interpretable and, more importantly, impactful.
Then back with your 2Q update over the summer, you also disclosed that you were adding a second dose to this study, and that was helpful, at least in allowing you to select the phase II-B doses. I guess, can you walk us through, you know, one, the decision to add a second dose, and then two, you know, how that was helpful for you to finalize.
Yeah.
Phase II-B dose selection?
The most important decisions that we have made at Kymera since we founded the company and me as CEO has been the selection for the phase II-B doses because those will be critical for enabling us to go into a registration study.
Yep.
We wanted to make that decision with as much data as possible.
Yep.
The initial study, it is true, was designed as a single dose, single arm, open label study to, again, demonstrate that we can degrade the target, we can refine the phase II-B doses, we can impact biomarkers, as well as an upstream biologics.
Mm-hmm.
We can impact clinical endpoint in the same range as upstream biologics. The goals were there. The goals continue to be the same. I think what we found after actually the first 10 patients, we felt like we knew enough about that one particular dose translation.
Mm-hmm.
That we had a unique opportunity with the time that we had to add another dose and get another data point in the translation from healthy volunteers to patient so that our phase II-B dose selection will be as data-rich as possible so that we will be absolutely confident that it was the right dose selection. To be honest, now that we've concluded the study, and obviously in December we'll share the data, I am still convinced that that was the right decision and it's allowed us to make the best decision possible on the phase II-B dose selection.
Yep. Is it a higher dose or a lower dose?
I don't know if we'll ever find out, actually. I think we'll find out what the two doses were and are.
Oh, you won't tell us what you're gonna say?
I don't even know. We'll see how we feel that day.
Okay. Okay. So then this is the question that you're gonna be continued, you know, people are gonna ask you as much as possible over the next month, I guess, is, you know, what is a good outcome then in the I-B? When you disclose the data in December, you know, what should we expect to see to really validate that you have, you know, replicated the efficacy of, of a Dupixent?
Yeah.
In a study?
I mean, let's start with saying that obviously a small study like this will not be able to replicate the efficacy of a drug that has been in almost a million patients now.
Mm-hmm.
I'll kind of break down in pieces. The end goal is to continue to tell the story that we have a potential of dupi-like.
Sure.
Profile in an oral pill, which is different than saying we have the dupi-like efficacy, which I think it's, you know, you have to have a larger dataset.
Sure.
To being able to credibly say that. I'm gonna break it down into the right pieces, I think. The first thing is success. What does success look like? First, that we have safety that is in line with what we've seen so far. This is an exceptionally competitive space, and there is only room with highly well-tolerated drug, in, especially in the oral arena where, you know, again, safety will continue to be paramount, that we can translate the degradation that we've seen in healthy volunteers to patients. Again, we've talked about the phase II-B , though, so I'll leave that out.
Yep.
Then, the beauty about AD patients, that with regards to blood biomarkers, that in most patients you'll see high elevation of baseline of many of, whether it's IgE, TARC, eotaxin. In the dupi study where, you know, the really, the biomarker that was mostly modulated in blood and that was measured was TARC.
Mm-hmm.
If you look at those studies, the baseline of TARC was quite high. We expect that if we're able to have patients with the same elevation of TARC at baseline, we need to see the same level of inhibition of TARC. We have absolute confidence in that because we've seen in all the studies we run so far that we can block IL-4 and 13 as well as an IL-4 receptor antagonist.
Yep.
We will look at also IgE. In four weeks, you do not really see big changes in IgE, but as always, we are very transparent with data. Then we look at biomarkers that we have seen in healthy volunteers like eotaxin that in the studies with dupilumab were not collected in AD patients, but we will continue to share that. We will have a comprehensive view of type 2 biomarkers in blood of AD patients. We will be able to compare the ones that were measured in the dupilumab study. We will go in skin. We will have biopsies at day 28.
Mm-hmm.
At day 28, we'll know the level of degradation in the skin. Also, we'll have the changes in the transcriptomic profiles after 28 days of dosing versus pre-dose.
Yep.
We expect to see changes on proteins downstream of IL-4 and 13. Again, we have done a similar experiment, a much simpler experiment preclinically. We have taken human skin cells and looked at transcriptomic changes compared to dupilumab, and we saw a high level of correlation. We continue to expect a similar outcome.
Mm-hmm.
With regards to clinical endpoints, again, we have two doses, so roughly 10 patients for each dose. What we're seeing is that we expect the clinical endpoint to be in the ranges of dupilumab.
Yep.
Just because this is day 28, small patients, you're on the steep part of the efficacy curve, hopefully, if you have efficacy.
Mm-hmm.
It is really difficult to do like a number-to-number comparison. We want the whole package of data to be comparable to what has been seen with dupilumab at day 28. Given the small ends, we are encouraging our investors to focus more on a continuous variable like % easy reduction rather than categorical endpoints where the impact on one or two patients on a 10-patient study can be significant.
Yeah.
Would have 10%. You know, we wanna see the data in all the different time points or endpoints, I should say, to be painting the picture that we painted so far, which is.
Yeah.
We have a drug that blocks the pathway as well as an IL-4 receptor alpha blocker like dupilumab.
You know, the other element here, obviously you have two doses, these small numbers, right? 10 patients per dose.
Roughly.
You know, roughly 10 patients per dose. You know, should we expect to see any sort of a dose response, whether it's on PD effects like STAT6, going back to, you know, the phase I healthy volunteer data?
Yeah.
At 50 milligrams or above, you were getting almost complete STAT6 degradation. Is, is a dose response possible here? And if not, is that concerning as we think about the II-B?
I do not know if I have said it in these settings, but, you know, first, when we discussed the second dose, we always said, I made this, I gave this example of, if you look at the healthy volunteer data, we have three buckets of degradation. We had the complete degradation, which were the 50-200 microgram doses, the 90%-95% degradation, which were the 625-2,500 microgram doses. And then you had less than 90% degradation, of which we only had 1.5 milligram as a dose representation.
Mm-hmm.
One could say, to me, if you have the two doses are from two different buckets.
Yep.
I would expect a dose response. If you were in the same bucket, you probably expect less of a dose response.
Okay.
Without getting into where our doses are, I, I guess that's what I would say.
Okay. So you've started your phase II-B study at this point?
Yes.
Can you talk a little about the design of the two B, you know, how that's, you know, going so far, global study, other considerations?
Yeah. The goal of our study is actually the goal for us, we feel the responsibility to run an exceptionally well-executed study. Our inclusion-exclusion criteria are designed, and they're on our website, and they're the ones that have been used by all developers of biologic drugs in the space. So EASI 16, BSA more than 10, Pruritus NRS more than four, et cetera. More importantly, it's actually designed and executed to have as high quality of a study as possible.
Mm-hmm.
We wanna have moderate to severe patients that, we understand, have AD, have moderate to severe AD that have the right severity, and that will be able to demonstrate fully each dose versus placebo, the level of activity that we can see. The beauty of our study is obviously it's a 16-week study that has a 52-week open label extension study.
Mm-hmm.
Not only will we see the activity and the safety of our drug for 16 weeks, but we will have, I believe, a full picture of also the long-term safety and activity of our drug beyond week 16. I think ahead of our first phase III study.
Mm-hmm.
We will have a full, I believe, a full understanding of the target product profile of our drug.
Can you talk about the rationale for allowing advanced therapy experienced patients, not just biologics, but also JAK inhibitors in the study?
The way that we've treated those is we've said, if you have responded to upstream intervention, whether it's an IL-4 receptor alpha, an IL-13, or even a JAK inhibitor, you've responded to the therapy, and then you have chosen to discontinue.
Yep.
Either for tolerability issue or because actually the insurance company coverage, you've changed insurance.
Mm-hmm.
So you've basically proven that, especially with the biologics, that, you responded to an IL-4 and IL-13 drug, then we don't have a scientific rationale of why you should not be on our study.
Yep.
For that reason, we feel like if you're a responder and you've moved on for a different reason, you should be on our, you could be on our study. And if you're a non-responder, where you clearly have.
Yeah.
Maybe different biology going on, it's probably not the right thing to do on the first placebo-controlled randomized study.
Makes sense. So you're, you're also on track to start your phase II in, in asthma in the first quarter of next year. What's left, you know, in, in terms of getting sites ready to initiate the study at this point?
It's on track, and these studies have been planned to be staggered start by, you know, a couple of months or whatever it will be, to make sure that the quality of our startup is optimal.
Yep.
There isn't any particular data or other things that we're waiting. This is really to optimize startup and execution of studies. I'm super excited about asthma. I think it's a place where we can change the lives of many adults and, more importantly, many children given this mechanism.
Mm-hmm.
It's another one that, we're obviously paying a lot of attention to.
Yep. Maybe, maybe pivoting now to IRF5. You know, I think for Kymera specifically, it's certainly not the indication folks are, the target folks are most focused on right now. But, you know, heading into next year, heading into the clinic, you know, why should we get excited about IRF5?
I think this target has been a top target in the immunology industry for the past five, seven years from my observation of the space and our own work. I think we are the first company to really unlock this target. This target is extremely difficult to target from a chemistry perspective. We have an exceptionally potent and selective degrader. This is one of the targets with the most compelling genetics data out there. There is strong genetics in lupus, IBD, and RA. This target is unique because it's extremely broad with biology. It's, you know, inflammatory cytokines like TNF, IL-12, 23, type one interferon, and also B cells and IgG production, but done in a very specific way in a subset of cell types.
Mm-hmm.
Dendritic cells, macrophages, monocytes, B cells, and only upon activation of particular stimuli. You have a broad mechanism, but also very specific, combined with strong human genetics. I think this is gonna be an exceptional program from the biology and translation perspective. I think we've shown in preclinical data that has the activity in lupus, as we've seen, and some early data in RA, but especially in lupus, is at least as good, if not superior, to all agents that are either approved or in clinical development as an oral drug. It's gonna be another important pillar.
Mm-hmm.
very co- as you see, complementary to a type 2 drug like STAT6. This is a very complementary mechanism.
With STAT6, you know, atopic dermatitis is probably the obvious first indication. Is lupus or RA, is one of them more obvious than the other in terms of, you know, rapid proof of concepts, you know, unmet need that makes sense for IRF5?
Yes. For IRF5, we believe the most mechanistically validated disease indication is lupus and other interferon-related diseases.
Mm-hmm.
I think that the team is focused on what is the other potential parallel or staggered both proof of concept or indication that could be done in a more accelerated manner.
Mm-hmm.
As you know, lupus does take longer given the need of long duration of studies and large ends needed to show differentiation from placebo.
Mm-hmm. Is the KT-621 program a good analog for how to think about how you will develop an IRF5?
I mean.
Is it phase I to proof of concept to phase II type of approach?
I think the way to think about it is, yeah, I mean, obviously phase I.
Yep.
It is possible that there will be a patient study before the phase I and the II-B .
Mm-hmm.
Also for IRF5. I, it likely will look different than.
Yeah.
The 621 phase I-B study.
Okay. Maybe briefly on IRAK4, you know, what is the current status of the new program with Sanofi and, you know, what does the path look like for that getting into the clinic?
Yeah. We know we've delivered an IND-ready, second-generation degrader, which we're very excited about, potent, good distribution, exceptional safety and specificity. Sanofi is on track to initiate the phase I study in 2026.
Mm-hmm.
and that's all we can say at this point.
I guess sort of with that, my last question here is, when you talk about cash runway, you know, what's embedded in those assumptions across, you know, STAT6, IRF5, and what are the potential milestones associated with Sanofi, Gilead that, you know, might come in the next 12 months or so?
Yeah. So the cash runway into the second half of 2028, this encompasses the phase II-B studies.
Mm-hmm.
For six to one, encompasses patient studies, with 579, encompasses going into the clinic with new programs.
Mm-hmm.
includes initiating phase three, at least one phase three for 621. You know, I think four does not include any milestones.
Yep.
From our collaborations. We believe we're on track for potentially multiple milestones next year.
Mm-hmm.
Across the Sanofi and Gilead collaborations, we like to, because we do not control those.
Mm-hmm.
We like to keep them as an upside case instead of being in the base case.
Great. Any final thoughts or questions from the audience?
No. I mean, thank you for, you know, we're very engaged with the community here. We have great meetings today. We're always available for follow-ups. It's an exciting time. I mean, we were excited about our program and the opportunities, but we also have, you know, we feel strongly the responsibility to do the appropriate drug development. You will see us focused on not only speed, but also quality going forward.
Great. Nello, thank you.
Thank you.