All right. Great. Thanks, everyone, for continuing to join us at the Stifel Healthcare Conference. My name is Brad Canino. I'm Senior Biotech Analyst here. Really happy to do the next fireside chat with Nello Mainolfi from Kymera Therapeutics. Nello, thank you for joining us.
Thanks, Brad.
Let's just start off with an overview of the key milestones you announced on the recent 3Q call, and how that aligns with your vision and strategy for Kymera.
Yeah, Nello. Again, thanks for having us. It's always great to be back. So, you know, just going back, Kymera was founded with the ambition of building, you know, a leading biotech company that would develop a new generation of medicines. And we believe that targeted protein degradation is a unique modality that can allow us to really push the envelope on biology, clinical investigations, and commercial opportunities. And so I think we continue to do everything that we were doing, and we've been doing, and we will continue to do, with that goal in mind: maximize opportunities and value that this technology allows us to do. So, you know, our first program, as you all know, is focused in immunology, an IRAK4 degrader.
So what we talked about two weeks ago on our quarterly call was that, you know, a successful transition from Kymera to Sanofi has allowed now that program to have started two Phase II studies, one in HS, hidradenitis suppurativa, and one in AD, atopic dermatitis. We also said that we received a milestone—at least a milestone was triggered on the HS study with the first patient dose, and then the AD study, we expect first patient to be dosed between now and the end of the year. We hope immediately. And so we're excited about, you know, having two programs in two meaningful indications where there isn't, in our view, an approved oral drug that has robust activity and a good safety profile.
So that's really the, let's say, the high level of TPP we're pursuing. We, you know, based on what you see on clinicaltrials.gov, the expected recruitment should be able to be completed by end of 2024, with data in the first half of 2025, that hopefully Sanofi and, and Kymera would be excited to share by that time. So that's, that's one, update. The second, you know, we, we reported on, on STAT3, at ICML. We had some, what we call a proof of mechanism data. So demonstrating, again, for the second program in the clinic, fidelity of translation from PK and PD and safety into human, in this case, patients.
And so we, on that call, on the second, we also had coincidental release of the abstract that we had for ASH, and I think the abstract talks about early signs of clinical activity. The cutoff date of the abstract was early, and so the cutoff date for the poster obviously will be beyond the July 10th. And so we hope to be able to share more, more data, both in terms of PK, PD, pathway engagement, but also antitumor activity in patients. So we're excited about, at least in the abstract, sharing a first proof of concept of a STAT3 degrader, where we saw activity, at least in one CTCL patient. And then we also shared...
So as you know, you follow us closely, we had committed to share, again, what we call a proof of mechanism data on our MDM2 program. Usually, our proof of mechanism data are focused on, again, target engagement, safety, PK. And we did so with MDM2. We just were, you know, quite positively surprised by the immediate clinical activity that we saw with the program in the absence of your typical heme tox that you see in MDM2 development programs. So we thought it would be worthwhile sharing some of the initial antitumor activity that we saw. Again, a patient for, you know, six months plus on study, with a strong PR, without, you know, any typical MDM heme tox.
So we thought it was worth sharing that, given that the next update will definitely be next year. And then we also talked about some pipeline and prioritization decisions that we made, and I think one that we shared was on our KT-413 program, our IRAKIMiD program. This is a program that was targeting a MYD88 mutation that is mostly present in diffuse large B-cell lymphoma. And our decision was, you know, driven by, you know, evaluation of the evolving landscape in oncology, both regulatory, pricing, and competitive intensity, including the fact that that area is now really well-served by approved therapies, especially beyond first-line, like CAR T and bispecifics.
And we thought that, as we've always tried to do, is invest our resources, both human and capital resources, on programs that have, you know, high impact. And so we decided to terminate that program and focus on kind of two areas. One, we saw an opportunities to extend our runway from second half of 2025 into first half of 2026, but also fund our emerging immunology pipeline that we will be disclosing early next year. As you know, we were the first TPD company to work on immunology program with IRAK4, and, you know, I will say we have turned a focus on IRAK4 that many other companies have followed, both large and small, which I think is a testament to the work that we've done.
And, you know, the data that we've generated with IRAK4 has validated the approach that TPD, so again, targeted protein degradation, can have a big impact in immune inflammatory diseases. And so we have doubled down since then, since, you know, 2020, and now we're at the, the, you know, close to initiating clinical studies with novel programs, and so it's, it's time to start talking about what is the expanding immunology pipeline. So we'll have an R&D Day on January 4th, focused on immunology, that will be, you know, disclosing new programs.
Yeah. And can I ask in that? I mean, we're, we're in a capital market space where a lot of other companies are shedding assets. You know, you have a pipeline already of three early-stage clinical assets. So what is the goal of the planned R&D Day? Is this when we're gonna start to see new named assets, new timelines to trial starts that we didn't expect before?
Yeah. So, you know, we, we believe that in order to fulfill our mission to, to becoming a company that takes protein degradation into a commercial stage reality with meaningful, differentiated assets, we need to continue to invest also in our discovery pipeline. And I always say often within Kymera, you know, our, our next generational program need to be at least as exciting as the existing program. So, the goal of the R&D Day is to disclose, you know, a, a couple of new programs that we believe address meaningful clinical opportunities in pathways where, where there is already been high degree of validation, both clinical and commercial, where we believe we can have a best-in-pathway drug, using TPD with a, an oral profile. And, so maybe we'll leave the detail to that, to that day, but that's, that's the goal of that disclosure.
Okay. I guess for investors that are watching a lot of other early-stage immunology companies decline in value by 50% or more in the past few months-
Sounds familiar.
How would you describe why Kymera represents a better long-term investment in this therapeutic space?
Well, I believe, you know, regardless of the volatility and my joke, that I think every company should be focused on maximizing value of their abilities. And for us, you know, we believe that, again, as I continue to say, targeted protein degradation has potential to change medicine, and the only way that you can maximize value of a novel platform is by deploying it against the right targets. I believe at Kymera, we've had a unique approach to target selection, which continues to be validated. Again, we've shown for four programs translation of PK, PD, and safety into the clinic in patients.
For three out of those four, you know, the ones that, that we continue, obviously, we have shown early proof of concept without toxicity being a limiting factor, in, opportunities that we believe are meaningful. And so we continue to focus on that. And so I think what has created, I'm not gonna talk about companies or specific, as, you know, specifically addressing your, your, your point, but I think what's happened generally, as it's happened in oncology in the past and now it's, it's starting to, we're starting to see in immunology, that, you know, we've had programs with a, an arguably undifferentiated profile going into the clinic and, and probably seeing that the undifferentiated profile is undifferentiated with data. And I believe you'll see from Kymera, and, and hopefully, you've always seen, that we always have a biological differentiation profile.
So we can articulate, hopefully, also in January, but so far we have that a degrader against target X will be differentiated because the biological and clinical output of a degrader will be different than either small molecule inhibitors and antibody or another pathway engager. So, you know, I think that has played out with IRAK4 so far, and we have high confidence that when we talk about the new targets, you will agree that that is the case for those. And so we're not gonna, you know, develop another... I'm not gonna name a name of targets, but another target that is being-
Mm
... pursued extensively without a clear biological differentiation.
Okay. I'm wondering, how much did the data and profile you generated from the Phase I study of KT-474, which was in HS and AD patients, influence your further prioritization into immunology?
Yeah, I mean, I would say our doubling down in immunology, actually, I think what has influenced the most has been the Phase I healthy volunteer data. That's just purely based on timing of it, right? If, you know, if we obviously, we had to wait for the patient data, it would have been last year. You know, we wouldn't have enough time to really build the pipeline that we now are going to disclose. But that has further validated the initial reaction. So I would say a few things. So when we started IRAK4, so the IRAK4 program started in 2017. We had our first protein degradation cell data in January of 2017. We were in the clinic in 2020, and, you know, showed data in patients in 2021, 2022.
So what we've learned along the way is how do you develop a degrader in immunology? So that means degradation across different cell types, kinetics thereof, distribution in tissue, safety, regulatory requirements. And then when we started to see how well-behaved this drug was, KT-474, if you recall, and actually I can plug our Nature Medicine paper that just was published a couple of days ago. This is the first TPD clinical paper that has been published. In that paper, you'll see how tight the data was in our phase I study and phase Ia study, where we were able to get 95% plus degradation in blood with extremely narrow error bar.
So we saw that the molecule was behaving so well, the impact on the pathway was so strong, and in fact, and then eventually also in patients, we saw initial exciting data. It just validated that this is a place where degraders can have a really meaningful impact. And, you know, while we haven't had the opportunity, probably never will, to run a head-to-head comparison with small molecule inhibitors, I think the totality of our data, both preclinical and clinical, point to a differentiation, both, you know, biological and clinical. And so that's where the confidence is coming from.
Got it. I think you make a fair point on the undifferentiated mechanisms that-
Mm-hmm
... we're seeing sometimes in immunology, but I also sometimes have concerns about just the ability to extract an effect size from some of these trials, particularly in HS. You know, how much of a risk do you see within that? Because that is one of your lead indications for KT-474.
Yeah.
You're kinda going in with a, you know, a 10-patient Phase I. You saw some activity for the drug, but if placebo outperforms, it could ruin everything. Like, how do you think about that?
I mean, the one thing I think is that we don't know the effect size of our drug right now, right? It's fair to say what we see out of, you know, the 10 patients-11 patients is encouraging, exciting early data that has nothing to do with what is the activity of a drug in a broad patient population. So I would make two points. First, I think it's a fair point. So, the profile that we're developing with Sanofi, and I should remind everybody, Sanofi is actually running those Phase II studies. We are curious and paranoid observers, we always wanna know everything about those studies. And, you know, they've been great partners so far, and I'm sure will continue to be the case.
So in those studies, you know, obviously for those two Phase II studies, the goal is to have power to evaluate the clinical activity. So I think they're powered enough to appreciate the actual clinical benefit of this drug in a broad patient population. Let's say, high-level TPP that we have for this drug in both HS and AD is to have an active drug with a good safety profile, with the convenience of obviously being an oral drug. We're not, at this point, trying to differentiate from biologics. Now, that doesn't mean that eventually we will not.
I think right now, our bar is we wanna show differentiation from placebo, which is the, you know, the first bar that we have to clear, and then have an opportunity to place that drug as we continue development in a treatment paradigm based on the landscape and the TPP, and the profile and label of our drug. We believe that an active drug with a safety profile, oral, is not present right now in the marketplace, and we don't believe there are many, let me be generous, that are being developed right now. So that's the profile that we have. You know, we have the fortune, you know, on not having to chase, you know, the next, for example, IL-17 drug, where, you know, you need to show differentiation because you're in the same pathway, same mechanism.
We believe that, you know, our approach is different.
Yeah. Maybe this would be redundant because I think you're, you're alluding to this, but I just wanna make sure I've, I've got that correct. So if this is successful in Phase II, should we expect you do the Dupixent or Cosentyx playbooks when it comes to rolling this into pivotal studies, or because of that Phase II target product profile, do you see differentiated avenues for development in pivotal trials?
I mean, unfortunately, I can't comment on beyond this study because Sanofi is both in charge of those, and I don't wanna say something that might be different. But I will say that we are focused on generating data that will more definitively answer the question of: Is an IRAK4 degrader active in HS and AD, and what is the effect size versus placebo? And, you know, I, I'm confident that if the answer will be positive, we will be very aggressively pursuing further development plans.
Okay. If we move on to KT-333 or STAT3, it would be helpful to better understand your goal in oncology, with this asset, with the recent data generated, and, and how you frame that amongst the doubling down in immunology-
Yeah
... like you said.
Yeah, yeah. So, so just let's go back. STAT3 , another key transcription factor, JAK-STAT pathway. Again, I, I believe, hopefully, I think people will agree, this has been probably one of the most well-characterized STAT3 agent in terms of specificity, activity, preclinical and early clinical activity. So we know it degrades STAT3 selectively. And now, in oncology, what we've learned preclinically is that there are tumor types that are in a, in a, let's say, a cell-intrinsic mechanism, are dependent on STAT3 signaling. And when I say cell-intrinsic, I mean that cancer cell exposed with STAT3 degrader will die. And those are mostly within the T-cell lymphoma leukemias. We've talked about CTCL, we've talked about PTCL, LGL leukemia as well.
And so for those indications, based on our preclinical data for those tumor types, we expect to see single agent activity in the clinic. And in fact, we were, you know, actually pleasantly surprised that even at DL2, which let's say it's probably below the expected degradation profile, but probably not by much, we have started to see antitumor activity. And so that's an avenue to be explored clinically. Single agent activity in those tumor types. What is for us, you know, exciting and intriguing is exploring this mechanism in both cell intrinsic and extrinsic nature, which means both what it does to cancer cells, but also what it does outside of the cancer cell. What we have shown preclinically is that in combination with a PD-1, you can actually see a synergistic effect that results in, you know, pretty strong antitumor activity.
Now in a Phase I study that we're developing now in a dose escalation, where we're escalating as a single agent, what does good look like? Good will look like if we can confirm antitumor activity as a single agent in heme tumors, and good will look like if we're able to see that we're changing, we're impacting tumor microenvironment in these tumors, and, you know, ideally measured by tumor biopsies and looking at these, you know, well-characterized signature that are that have been shown and validated to be sensitizing tumor to PD-1.
So, and I will say that our commitment to having a high bar in clinical development, that continues to be also in oncology, going back to your second part of the question, will require us having opportunities to go and develop this drug in both heme as well as solid, in order to be meaningful enough for us to continue to deploy capital.
Yeah. Now, what else have you observed in this Phase I data set about the profile of the drug that you think is relevant for an immunology push for this asset? Because you've got STAT3 listed for immunology and fibrotic diseases on-
Yeah
... the pipeline as well.
Yeah. So, you know, I, I think, you know, again, going back to the mechanism, we were the first one to evaluate STAT3 depletion in the industry. And so there was a lot of exploratory work that we did on the biology and on the safety of this mechanism, both in oncology, outside of oncology. We've reported on immunology years ago now at meetings and conferences. The posters and presentations are out there. What we have learned, that I've said this last time, and I cannot add too much, or last time, meaning in one of these venues, that...
What I cannot add more than what's in the abstract and from the ICML presentation, but what I can say is, the one thing that we were very focused on was the PK/PD and safety profile. How the drug behaves in the central compartment, in immune cells, how the drug behaves in terms of kinetics of degradation and recovery, and what is the safety that we've seen? And I think all of that continues to be extremely supportive of a STAT3 degrader, also beyond oncology. As you know, this is an IV drug, which is not a route of administration and formulation we're interested to take in outside of oncology. And so again, the work has been going to exploring out, you know, what are the route of administration that we can adopt that are not IV?
Yeah. Okay. Maybe on to KT-253 MDM2. You pushed out nine patients' worth of data for this on the last call. I think you-
I thought it was less.
Was it?
No, no, I think you're right.
If you, you know, walk around and talk to people here, including executives, I think they would tell you that was probably a very dangerous idea to do in oncology, to have such a small data set in a market like this. What gave you the confidence to present such an early look for this mechanism and drug?
Yeah, I mean, look, it depends what the context of our data. Hopefully, you haven't heard us say we have solved this, the MDM2 problem, or we have a 100% response rate in Merkel cell because we had one patient, right? So the context of our data were. So we had two goals for this program. One goal was, can. You know, this is the fourth program, can we, can we replicate and translate the preclinical profile? Because if we're not able to do that, we don't have a program, because, as you know, we have this infrequent dosing that requires high Cmax and high impact on MDM2 pathway for the first few hours, and then clearance of the drug and of, of, MDM2 degradation soon after that. So do we have the PK/PD to do that?
Is that supporting of our thesis? So our thesis is, if you degrade MDM2, you commit cancer cells to death in the first few hours, and then you can dose after three weeks because that's enough to drive strong antitumor effect, and it's enough not to have bone marrow-derived cells, cells commit to apoptosis, and so die. And in fact, we've seen preclinically, we can have strong antitumor effect without neutropenia and thrombocytopenia. So the reason why we actually, as you know, for example, if you kind of trace all our communication, when we showed at ICML, we showed data from those levels, too, but we did not talk about our partial response.
Mm-hmm.
Because we felt we wanted to generate more data to have a more coherent narrative. Now, obviously, that had to go into the abstract, but, you know, the presentation will be in December. The reason why we actually shared this early data is because it started to validate our thesis that you can differentiate toxicity from anti-tumor effect, which has never been done in this field.
Mm-hmm.
By no means I'm saying that we've solved that problem, but the fact that it validates our thesis, we felt it was too important not to share. Because the next time that we'll share will be probably roughly, you know, for at least not any time in the next six months, and we felt that this was a meaningful material piece of information that we felt uncomfortable not sharing. And I just want to repeat, we have those, the patients, who are now, you know, seven months, still on therapy, still with a response, without neutropenia or thrombocytopenia. I don't believe that has probably ever been shown in the MDM2 space. Again, it's one data point, although we had another patient that was on study for also six months without neutropenia.
We've had patients on the second dose levels that we haven't reported on activity, but we've reported on safety, so neither there we've seen neutropenia or some thrombocytopenia. So I think we wanted to say, "Look, not only we're showing proof of mechanism, but we're seeing our thesis playing out in front of our eyes." I will say that in order to confidently say that we solved the MDM2 problem, we need to generate more data. I want to be clear, and I agree with you on that.
Yeah. I think your, your confidence is showing through into actions as well, because you opened an AML cohort-
We have, yes.
... pretty rapidly. I guess, do you expect to see single-agent activity in this disease and for it to be robust? And then, what's the broader vision of MDM2 in AML?
Yeah, I know. So, yes. No and yes, but I will answer the question. I was thinking about three things at the same time. So first answer is, we've seen preclinically extremely robust activity in AML. As you know, AML is not an easy place to develop drugs. I think everybody knows this. But it's still an unmet need, and patients unfortunately, you know, don't have a great outcome in many cases. But we've seen, as a single agent, robust activity, so much so that we've seen these regressions in preclinical models after one dose for 120 days. So clearly, the mechanism has an impact in this disease. We've seen it in PDX. We've run mouse clinical trials in AML, and they've been impressive data.
We've also seen in combination with venetoclax activity, and then we've seen also in venetoclax resistance, we've seen activity. So we have confidence this is a meaningful mechanism in AML. The broad picture here is: What is the development path for this degrader? And again, for us, in order to be a program that we want to be excited about, we need to have a broad development plan. And I think what we're excited that we're seeing is a signature of sensitivity that actually seems to be consistent across several tumor types. So obviously, it's not P53 wild type. That is necessary, but not sufficient. But we would love to be able to have a tumor-agnostic sensitivity signature that will allow us to develop this drug much more rapidly.
And I can't say that that has happened completely yet, but the data that are emerging are pointing to a genomic signature that is common across all these tumor types. And so in our update, there will be at some point next year, not earlier than middle of next year, let me say that, we hope to be able to give an update on both studies, the solid tumors and AML, and if we can, ideally combine that with a disclosure around our sensitivity signature, and then talk about what is the, let's say, later development plan for this asset in oncology.
I see. Okay. Yeah, that was gonna be one of my questions around a biomarker approach here. I guess, as you kind of teased a tumor-agnostic approach, you know, oftentimes we think of those as monotherapy approaches. And obviously, that's important for a smaller company, but this mechanism, I would assume, overlaps with a lot of other potential targets you want to hit the tumor at the same time.
Yeah.
So, do combinations start to come into play?
Yeah, it's.
-as well?
It's a great question because, I mean, you just went right into the core of this program. We believe that this mechanism with a degrader approach has a real potential, a single agent in a subset of tumors, in a wide variety of tumor types. You know, I even know the percentage, but I can't share it because it might change between now and when we're done with the work, but it's a meaningful opportunity. Now, probably, what the opportunities in combination could be orthogonal to that, and that's how are we gonna do that? You know, as you see, MDM2 small molecule inhibitors have taken a bolder, you know, combo approach. I think because of the challenges that they faced.
I think we owe it to the mechanism that we, for now, prioritize the single agent path, but the combo has to be part of the broader development plan.
Yeah. Okay. Unfortunately, we're out of time, but Nello, this has been fun, as always.
Always.
Thank you so much.
Thank you, Brian.
Thanks for listening.
Thanks, everybody.