All right, good morning. Thanks, everybody, for joining Jefferies Healthcare Conference in London. My name is Clara Dunn. I'm one of the biotech analysts here at Jefferies, and I'm joined by Chief Executive Officer Nello Mainolfi and Chief Financial Officer Bruce Jacobs from Kymera. Welcome.
Thanks for having us.
Maybe just to kick things off, could you talk about, maybe for those folks who are less familiar with the story, what Kymera is focusing on right now? What has kept you busy for the past year?
Yeah, maybe just to go a bit back in the history of the company. We founded Kymera about nine, nine and a half years ago. The ambition has always been to develop a whole new generation of medicines using targeted protein degradation. This modality allows you to go after targets that have not been drugged before or drugged fully. The goal has been matching the power of the technology with the potential of the target and invalidated pathways. We spent the first few years working in both oncology and immunology, and then about five years ago or so, decided to focus almost only on immunology.
The opportunity we see, which we believe is unprecedented, is that we can develop, thanks to, again, as I say, the power of the technology, a new generation of medicines that have the efficacy of a biologic and the convenience of an oral drug. When we focused on this strategy, we went and thought about what are the best validated pathways with mega blockbuster upstream biologics that lack an intracellular oral solution. Obviously, type II inflammation is one of those, IL-4 and 13. We obviously looked at IL-1 biology with IRAK4. We look at, can the B-cell biology, type I interferon with IRF5. We have several more programs that we have yet to disclose that we're also very excited about. That's maybe I'll pause here on the high-level strategy of the past few years, and maybe we can get into more specifics.
Yeah, as you mentioned, Kymera's platform, and I just want to maybe touch on this platform a little. I mean, there are other companies working on targeted protein degradation as well. How do you view the differentiation of your platform, and what kind of evidence in the past have given you this confidence of the translation of your preclinical work to clinical work as well?
Yeah, you know, I like to go back to maybe basic principles. What we're trying to do here is to develop medicines. What the platform allows us to do is to have an engine of continuous innovation that is replicatable and reproducible. That's how I think about what we're doing at Kymera. The capabilities we built are building medicines, making medicines using protein degraders. What are the key things that I believe differentiate our approach? One is we have taken, some would say, a bold strategy to go after targets that have not been drugged before. In order to do that, you have to identify small molecules that bind to these targets that have, in many cases, like transcription factors that are almost the majority of the things that we work on, transcription factors that have evolved not to bind small molecules.
We have to find a way to bind to these transcription factors. That's a key capability, finding unique small molecules. The second capability is making degraders that have the potency, the specificity, the DMPK properties to be behaving like in the human body, like, let's call it, traditional small molecule. The third capability is being really the best at translating preclinical data into the clinic, understanding the tissues, the organs, the kinetics of our drugs in these tissues in preclinical species and translating into humans with high level of fidelity. The fourth, I will say, is selecting the right targets. I think every technology, every platform modality lives and dies by the type of targets that the company decides to go after.
For us, it's degrading the targets because we believe we're going to have a highly differentiated asset and not because we can degrade a target, because you can degrade most targets. I would argue probably you won't be able to generate highly differentiated drugs for all targets.
Kind of just to add on selecting the right target, I mean, you've spent a lot of efforts on STAT6, and that has been the recent focus as well. Obviously, you have the phase 1b Atopic Dermatitis data coming up. Maybe just take a step back and tell us why STAT6 is such a compelling target to you and what makes it really important to your strategy as well.
Yeah, again, I go back to our philosophy is targets that have not been drugged or drugged well in pathways that have been highly validated, targets that ideally have strong human genetics in diseases and target population that we believe can impact millions of patients in the world. Those are our four pillars of target selection. I think if you use that very rigorously, there are very few targets that fit this profile as well as STAT6. It's a traditionally undrugged transcription factor. Obviously, we have not invented STAT6. I would love to say that, but actually, nature invented STAT6, and it's been on the target list of many companies for the best of the past 10 years, given all the work that has been done with the Dupilumab.
I think what we have done at Kymera is demonstrate how you can target this target selectively, specifically, and potently. Going back to how we think about targets, STAT6 is the key specific transcription factor that is responsible to propagate the IL-4 and 13 signaling. It is actually recruited to the receptor, IL-4 receptor alpha, which is the target of Dupilumab, is phosphorylated, and then goes to the nucleus to translate the signal. It is specific to this biology in a pathway that has been validated by the most successful drug in the space, which is Dupilumab, which has been dosed to a million patients in a world where there are more than 100 million patients that suffer from type II diseases.
Not only is this a perfect target because of the pathway validation, the human genetics, and the opportunity of using degraders to go after it, but more importantly, it is the right target because there are millions of patients in the world that have no access to advanced systemic biologics, and we can change the paradigm with an oral drug for STAT6.
This is a very exciting target, and we've seen maybe STAT6 inhibitors as well. Could you outline kind of key differences between STAT6 degraders versus inhibitors?
Yeah, you know, this is a simple concept. We've been working with small molecule inhibitors for the past century. I think in the past maybe 20, 30 years in which we've got more sophisticated on developing small molecule drugs or drugs in general, I think we've tried really, really hard to find inhibitors for intracellular targets that would be able to replicate the biology that we've studied that has been done mostly with upstream cytokine blockers. I think what we've learned, and this is applicable across most disease areas, but for sure in immunology, is that when you can target a particular target with a small molecule, what you're not able to do with small molecules almost ever is block the function of the target completely 24/7.
That is just because the expression of this target that usually are in the nanomolar, single digit, double digit, triple digit nanomolar requires a drug exposure that is extremely difficult to achieve with once-a-day oral drug. Actually, walking the line between the safety of the drug with the exposure of the drug with traditional small molecules is very difficult. With a degrader, the beauty of degraders is not only that we can go after targets that are difficult to block with small molecules or even impossible to block, but it is the fact that we can do it in a way we can bind to a target neutrally, so we do not have to block its function. We do not usually have off-target binding to other proteins. Importantly, we can have a catalytic effect.
We need a small amount of drug for a short amount of time to completely remove the target. We can dose once a day. We can potentially dose less frequently than once a day. It allows you to basically, in this case, degrade STAT6 completely with very low exposures, with very short exposure of your drug. We have data that shows preclinically that in order to compete with the efficacy of an upstream biologic with Dupilumab, you require 90%+ pathway blockade. I would say even more than that. We believe that's achievable only with the once-a-day oral degraders and not with other modalities.
Maybe let's talk about the healthy volunteer data you released in June this year and among all the biomarker analysis. What kind of, what are the findings that you found most meaningful and exciting and kind of give you the confidence for this KT-621 potential in atopic dermatitis patients as well?
I always think about completing the translation of a robust preclinical data set into the clinic for all the work that we've been doing in 2025 at Kymera. Preclinically, we've shown if you degrade STAT6 90% plus, you're able to block downstream biomarkers, and you're able to impact disease endpoints in a way that is comparable, in some cases even superior, maybe numerically, to what Dupilumab has shown. We are the only company that has actually published data of head-to-head comparison with Dupilumab in preclinical studies. Our first goal of the healthy volunteer study was to demonstrate that we could safely degrade STAT6 at 90% plus. What we're able to show is that we were able to achieve 90% plus degradation with almost all doses that we tested in humans.
Actually, the only dose that reached less than 90% was a cohort that we had added at the end of the study of 1.5 milligrams to capture the lower end of our dose response curve. Clearly, we showed we can degrade the target well. For doses at or above 50 milligrams, we degraded STAT6 completely in both blood and skin. We also did it extremely safely. In fact, our safety profile was comparable to placebo, and that's consistent with the safety we've seen preclinically. We also asked the question in healthy volunteers where Th2 biomarkers are not elevated at baseline. Obviously, big caveat, can we show that STAT6 degradation blocks the pathway enough that we can measure impact on these biomarkers?
We actually would say we were pleasantly surprised that even in healthy volunteers, we could block, for example, TARC into the 30% range, which is quite similar to what Dupilumab has shown. We also looked at other type II biomarker like eotaxin-3, which has not been measured by other companies, but we showed very robust inhibition in the 60% range with our STAT6 degraders. I think the take-home message from the healthy volunteer is there are three key messages. We can degrade the target fully. We can degrade the target safely. That target degradation leads to pathway inhibition that we believe demonstrates in healthy volunteers that is comparable to using an upstream biologic.
That being said, as we head into the December readout from your phase 1b Atopic Dermatitis, maybe what should we expect there? What kind of data are you going to show? Maybe just help us define what will be the winning case for Kymera.
Yeah, I just want to say that our main goal is to get to registration with this drug as quickly as possible for the fact that, again, there are millions of patients without an accessible, convenient, effective, and safe oral option. All our development strategy is based on how quickly we can get to registration. We had a short opportunity here in 2025 to test the KT-621 in the patient population. We decided to use Atopic Dermatitis because it is the patient population that allows us to answer many questions, even in a small study. The questions that we wanted to ask were, can we degrade the target in blood and skin as effectively as we have done in healthy volunteers? What we had, the beauty of having AD patients is that you have elevated pathway expression and elevated STAT6 level in skin.
Let's call it we have a higher bar to reach the needed degradation. We wanted to be able to answer that question quickly. We wanted to use this small data set to inform our phase IIb study design, including the doses that were selected. That was another important point. We wanted to demonstrate in a much more robust manner beyond the healthy volunteer data that by blocking STAT6, and again, in our case, degrading STAT6, we can block downstream Th2 biomarkers as effectively as has been seen with upstream biologics. We wanted to also demonstrate even only in 28 days that the degradation of STAT6 that blocks IL-4 and IL-13 as measured by Th2 biomarkers has an impact on clinical endpoints that are both measurable and generally comparable to what has been seen with upstream biologics like Dupilumab.
Obviously, the study is not powered to do a, let's call it a head-to-head comparison. The study was really designed around biomarker changes. We know, for example, if we use TARC as a biomarker, we know that if we have TARC at baseline in our patient in the range that has been seen with previous Dupilumab studies, we expect to see the same level of TARC inhibition. We will also look at other biomarkers in blood and skin. For clinical endpoints, it's really difficult to do cross-style comparisons in general, but we expect to see an activity that is robust at day 28 that is in the range of what has been seen with upstream biologics given the biology of this target.
As you mentioned, the phase 1b is to kind of facilitate the dose selection for phase 2b. This question might come up very often that you added the second dose for phase 1. Maybe just walk us through the decision-making process for you to choose the phase 1b dose. Why did you decide to initiate a phase 2b before maybe you announced the data for phase 1?
Yeah, so very simple, actually. I know this is a question that has come up in the past. One of the goals, as I said earlier, of the phase 1b was to inform our phase 2b dose selection, given that it's probably the most consequential decision that we've made at Kymera to date. We had an opportunity, given how quickly we were enrolling in the study, that after, let's say, half of the patients were enrolled, we felt like we had enough information on one dose that we thought it would be extremely valuable to have some more information on a different dose to further inform with more data our phase 2b dose selection. It was a simple kind of drug development rule of you can project a dose response curve with more than one point.
Having two doses will allow us to project our dose response curve in patients much more robustly. With regards to initiating phase 2b before disclosing data, obviously, the whole phase 1b is not technically on critical path to initiate a phase 2b study. In fact, there are companies that go into a dose ranging study without phase 1b data. We wanted to have enough data from the phase 1b, again, I'll say it again, to inform our design and selection of the phase 2b. Once we felt we had enough of that, we initiated the phase 2b startup process. For us to disclose the data, we have another important rule at Kymera. We try to release data when we have the totality of the data and not partial data.
In order for us to have the totality of the data, it just takes us actually a few more weeks, and then we'll be able to share the data in December.
We know that Atopic Dermatitis patients nowadays tend to have maybe present less severe disease compared to maybe a decade ago. How does this involving patient baseline complicate? I understand cross-crowd comparison is always difficult, but with that in the context, how should we think about the comparison?
Yeah, maybe just a small clarification on your statement. Disease severity has not changed over time. What has changed from the Dupilumab study is that when the Dupilumab was developed, there were no drugs approved. In the current landscape, there are several drugs approved. The more severe patients tend to be put on a systemic biologic, especially in regions and sites that are often used in these clinical trials. I would say in the world, patients are still underserved and undertreated. Generally, in these places where we do clinical trials, especially in the U.S., there is much more access to systemic advanced biologics. What that has done naturally has changed the patient population to a slightly less severe than it was done in the past few years.
I think the important thing that makes us feel pretty good about being able to analyze the data and contextualize the data is that if you look at the Dupilumab performance in more severe versus less severe patients, the treatment size, the effect doesn't change materially. Whether you have a baseline EASI of 29 mean or 25 mean, which is really what's happened in the past few years, based on the Dupilumab historical data, we haven't seen material change. That should allow us to contextualize the effect size regardless.
What other opportunities you might be considering beyond Atopic Dermatitis?
You know the KT-621 is a drug for type II diseases. We like to think at Kymera, and if you talk to people in the space, that this is a drug that treats all diseases that have allergic type II inflammation as a driver. So that's atopic dermatitis, asthma, eosinophilic asthma, eosinophilic COPD, prurigo nodularis, EOE, CSU, and many others. I think Dupilumab has been approved in eight. I think eventually it will probably be approved in 10 or 11 indications. We are focused our development plan to run two dose ranging phase 2b studies in parallel, Atopic Dermatitis and asthma. This will allow us to hopefully identify a phase 3 dose that can be used for atopic dermatitis and all the other derm indications and for asthma and all the other respiratory indications.
This, we believe, would allow us to have the broadest development plan, but also the one with the fastest path to registration. The sequence and how much is done in parallel versus sequence is something that we'll discuss as we get closer to phase III studies.
For the last few minutes, I also want to talk about the other programs you have and maybe IRF5 program. Maybe just walk us through the program and what's the current development priority for this one.
Yeah, so IRF5, another transcription factor, undrugged as it was STAT6, still is STAT6 until a first drug is approved. It targeted that as one of the most elegant and robust genetic associations between a protein and diseases. If you look at the genetic association of IRF5 with lupus, it's one of the strongest out there. There is also strong with RA and with IBD. The biology of IRF5 is actually quite interesting because it's specific to particular cell types, dendritic cell monocytes, macrophages, and B -cells. It's specific to a particular stimuli, TLR7, 8, 9 mostly, but it's very broad. It impacts inflammatory cytokines like IL-6, TNF, IL-12, IL-23, type 1 interferon, IgG in B -cells. It allows us to be a very strong anti-inflammatory effect, but in a very context-specific manner.
When you triangulate the biology, the human genetics, and our preclinical data, you can see emerging a few diseases that we're focusing on. Lupus and all, I would call them other type I interferon pathologies. As I mentioned, based also on the human genetics and our preclinical data, RA and IBD, for which we have some early exciting data that we haven't shared yet, waiting for the right opportunity. How we're going to sequence and prioritize indications is something that we'll discuss more next year. What I can say now, we've completed IND enabling studies, also in this case without any adverse events. I don't remember how many programs in a row now we've seen this profile. We're going to start our phase I early next year.
We're going to have data from the phase I healthy volunteer study also next year. We'll hopefully also have lots of conversations about that target going forward.
Lastly, on other preclinical asset, you obviously have some partnership on that. Maybe give us a quick snapshot on that and what's your latest thought on potential other partnership opportunities?
We have an exciting preclinical pipeline first that we plan to disclose as we get into the clinic. Hopefully next year, we'll be able to talk about another program. For our partnership, we have a partnership with Sanofi and Regeneron for the second generation molecule. We'll start phase 1 next year. We have an exciting partnership that speaks to the power of our platform to develop not only heterobifunctional degrader, but also molecular glue. We have a CDK2 specific molecular glue degrader with Gilead that also we hope to give an update next year as the program will hopefully transition to our partner.
Lastly, remind us your cash position.
Bruce, do you want to take that one?
On the home stretch, yeah. We have just shy of a billion, I think about $980 million as of the last quarter. It takes us out into the second half of 2028 and fortunately through many of the critical inflection points that we talked about here, the phase 2b's for AD and asthma, IRF5 program, and so forth. We have been fortunate to have a great committed and strategically aligned group of investors supporting us along the way.
Great. Thanks, Nello. Thanks, Bruce, and thanks everybody for joining us. I will wrap up our session here and enjoy the rest of the conference. Thanks, everyone.
Thanks, Clara.
Thanks.