All right. Can you guys hear me? Is that on? Okay. There we go. All right. Welcome, everyone. It's Gavin Clark-Gartner here with the Evercore ISI Biotech Research Team. Really happy to be here with Nello Mainolfi, who is the CEO and co-founder of Kymera Therapeutics. Nice to have you here.
Thanks. Thanks for having us.
Yeah, absolutely. So maybe just a good place to start for those who are less familiar with Kymera. Would you give us a quick overview of everything that's been going on, where things sit today?
Yeah. So Kymera is a company that was founded on the premise of targeted protein degradation. This is a technology that has the ability to combine the flexibility of small molecule drug development and the power of genetics-like knockdown, so we can degrade disease-causing proteins with oral small molecules. So the company has been founded seven years ago with the goal of building a fully integrated biotech that eventually will be able to discover, develop, and commercialize degraded drugs. We focused on targets that are in pathways that have been validated, where targets have ideally human genetics validation, but have not been drugged or drugged well with other modalities, where protein degradation will provide a unique technological unlocking solution.
And ideally, and more importantly, as of recent, we believe in more strongly that, you know, we have to be working in areas where there are meaningful, both clinical and commercial opportunities, where, you know, we can really bring to bear the power of protein degradation. So we have several clinical programs. We have an IRAK4 program that is in phase 2. This is in partnership with Sanofi. We've developed that program from inception to end of phase 1, which included, obviously, a comprehensive preclinical package, plus a comprehensive phase 1 study that included both healthy volunteers and HS and AD patients, demonstrating both proof of mechanism and early proof of concept.
We have a STAT3 program in oncology that is focused on this particular asset, KT-333, in oncology, going after heme malignancies as a single agent and potentially a combo agent in a variety of solid tumors. And then we have an MDM2 degrader, which we believe is the first time that we can fully unlock the power of p53 biology in p53 wild-type tumors, and that's also in the clinic with both STAT3 and MDM2. We showed early both proof of mechanism and early proof of concept in patients. We have an expanding pipeline that we will be discussing in an upcoming R&D day.
Sounds great. You recently deprioritized one of your oncology programs and have new targets coming in oncology. Maybe just from a high-level strategic perspective, you can kind of level set on focus between different therapeutic areas.
Yeah, it's a great question. So I, I think maybe philosophically, I just want to reiterate, you know, our, our target selection has been guided by, you know, those, those key principles that I outlined earlier, pathways with validation, undrugged nodes, meaningful opportunities. And, and I think that is a bar that we want to have across our pipeline. You know, for that particular program, KT-413, which was an IRAKIMiD degrader, dual degrader of IRAK4 and the IMiD substrates for mostly MYD88 mutant lymphoma, I think the decision was driven by the evolving landscape in that patient population, where, you know, there's been, several approved drugs, even in late line therapy, that are quite effective.
Obviously, the evolving regulatory landscape, as well as the pricing, the evolving pricing paradigms that, you know, have made, to be honest, for a company, or I would say probably for any company at this point in time, extremely challenging from the business perspective, to deploy resources in a program that had limited upside. And so we decided to, you know, terminate the program and actually use those resources for both extending our runway from second half of 2025 into now first half of 2026, but also continuing to invest in our emerging immunology pipeline.
So going back to your question about focus, I would say that, you know, we believe that there is a future, the future in immunology will have a unique opportunity to develop a series of oral degraders that can provide meaningful therapies in a biologics-dominated space. And we believe that the time is now in immunology for degraders, but we also believe that there are meaningful opportunities in oncology. We believe that oncology is, I would say, even for degrader, a much more competitive space, where the path to value creation has to be very clear, and so we have a really high bar in that space also.
I think for our resources, we intend to focus, you know, quite heavily in immunology and have also a high bar for what we want to take on our own forward in oncology.
I think that's well said. All right, so zooming into the MDM2 program a little more, can you just remind us what the early pharmacodynamic data has shown, and what your target levels of knockdown are? It may be helpful to kind of recap the mechanism.
Yeah, I mean, you know, p53 is one of the most characterized tumor suppressor gene, present in more than 50% of human tumors. And I think there is human cancer genetics data that shows if you knock down or knock out MDM2 in p53 wild-type tumors, you'll see high dependency and death in the absence of MDM2. And I think we probably wrongly assumed that using an inhibitor of MDM2-p53 would be able to replicate cancer genetics, and we've learned that actually that is not the case, as actually often, it's not the case.
We've seen that inhibition of MDM2 p53 can upregulate p53, but also upregulates more MDM2 transcription, and this leads to this feedback loop that small molecules have had a hard time overcoming because the stoichiometric pharmacologically, they have a stoichiometric pharmacological mode, and so you need more small molecule to fight more MDM2 generation. I think it's fair to say that the separation of activity and safety has been minimal at best. What we've been able to show with a degrader is that you can catalytically degrade MDM2, and so you overcome the feedback loop, which drives cells into a rapid apoptotic response and leave healthy cells in a different state that can actually recover over time. We can dose in a pulsatile manner, so once every three weeks, and this maximizes efficacy preclinically and safety.
Actually, we were quite pleasantly surprised that even our first patient on the study, a Merkel cell patient, was able to see benefit from our MDM2 degrader at the first dose level for more than six months, having a response without any signs of your typical MDM2 tox, which is usually bone marrow-derived tox, thrombocytopenia, or neutropenia. Pointing out to the fact that our thesis around building a degrader program from MDM2, which was building a therapeutic index, is playing out in the clinic. In terms of pharmacodynamic response, we, you know, we elicited an extremely rapid degradation and apoptotic response. So much so that we actually were not able to follow the degradation of the target 'cause that happens in really the first few hours.
So we have a surrogate downstream biomarker, which is GDF-15, which is a well-characterized MDM2 downstream gene, and we see a really strong upregulation of that gene over a course of the first week of dosing, and then obviously recover to baseline. And that is sufficient to drive this strong antitumor effect that we see already on dose level one.
Any expectations that you're willing to lay out for some of the data we'll see in 2024?
Yeah. So for us, it's critical for this program to accomplish two things. One is the full validation of our degrader thesis, which means that we see activity in the absence of dose-limiting toxicity. And so while I said just a minute ago that we've seen it on our first patient, you know, it's unscientific to say that one patient is sufficient to make that conclusion. So we wanna see that being replicated as we continue to dose escalate. And then, the most important, I would say maybe equally important aspect of this program is the ability to have a patient stratification biomarker. As you... As I mentioned earlier, p53 wild-type is necessary, but it's not sufficient for us to select patients. We wanna select patients that are extremely sensitive to this degrader mechanism, and I can give a spoiler already.
That's not all p53 wild type patients, but we are seeing preclinically a very intriguing signature emerging from a mouse clinical trial that we've been running in the past few months, where, you know, we're implanting tumors from patients directly into mice and look at responses over time. And we're seeing an emerging signature of sensitivity that seems to be shared across several tumor types, including several solid tumor types. And so our ability to tease out this sensitivity biomarker may be retrospectively apply in our dose escalation study, and then so share data in 2024, maybe middle, midyear or beyond, showing both clinical activity and this, sensitivity signature that we ideally wanna be using going forward, will be a great outcome of the next few months for this program.
That sounds good. Switching gears and going over to STAT3 transcription factor, can you just remind us why this applies to both oncology and immunology?
Yeah, I mean, you know, STAT3 is probably one of the most well-studied and characterized transcription factor, has been, you know, subject to probably 20-30,000 publications, and shown as being an oncogene in some context in oncology, being immunomodulatory in some context in oncology, and being an immune regulator in inflammation. And so we decided to, for our first molecule in this, in this program, KT-333, to evaluate it in, in heme and solid tumors, going after actually two different thesis. In, in heme malignancies, especially T-cell malignancies, where we see a clear cell intrinsic mechanism where depletion of STAT3 leads to a strong antitumor effect. And so we are now dosing patients with T-cell malignancies, where we hope to being able to replicate our preclinical data, where we saw a robust antitumor effect.
in that patient population. And then there is also another aspect, which is maybe more cell extrinsic, which is regulating the tumor microenvironment. We've seen preclinically this interferon gamma signature, which has been published on as being a marker for anti-PD-1 sensitivity. And so we'd love to be able to also see in tumor biopsies, our ability to also not only have a cell-intrinsic mechanism, but also a cell-extrinsic mechanism, an immunoregulator mechanism in oncology, that we can hopefully exploit later in development in combination with other agents, especially, we've seen good synergies with PD-1. So for the dose escalation, expectation is to see, hopefully, antitumor activity in T-cell malignancies, and then a biomarker-driven signature to then further explore solid tumors in combo as we continue the program.
For your oncology trial, maybe just remind us how STAT3 degradation was actually measured. Was it human whole blood, looking at any different specific cell types?
Yeah. So, we had the luxury of having both flow as well as mass spec data on samples that we take from patients. Usually, we look at—you know, we take a blood and then look at PBMCs, and we demonstrated that we can knock down the target at or even beyond 90% in some patients. Around 90% is our target degradation levels. And I think preclinically, we've shown that degradation in blood, in the central compartment versus a tumor, was consistent, roughly consistent. And so we'd love to be able to show also in the clinic, if we're able to take to have some tumor biopsies, that what we've seen so far in the blood can be replicated in tumors in term, in terms of knockdown of the target.
Got it. And for some of those other downstream pharmacodynamic markers, I think you guys have noted CRP, SAA, SOCS3 in your slides before.
Yeah.
Yeah, I mean, so what is the level that you're looking for there?
Yeah, I mean, I think as if you followed us, we've always had pretty robust PD campaigns in our phase 1 and including upcoming phase 2 studies, where I think it's important for us to have robust target engagement and impact on downstream biomarkers. As we mentioned, for MDM2, we're looking also GDF-15. For STAT3, we know STAT3, being a key transcription factor, has several genes downstream of it. And for us, demonstrating consistency between knockdown and downstream biomarker just gives us confidence that we're having the type of pathway effects that, you know, should lead to a clinical benefit. And so I don't know that we have a target for those downstream genes, but we love to see consistency between the knockdown and, let's say, SOCS3, which is a well-known gene downstream of it.
Or, for example, CRP, which is not directly a gene downstream of STAT3, but is a biomarker of that pathway, like IL-6. JAK-STAT pathway is a well-known downstream marker that, you know, is actually used extensively in clinical chemistry. And so actually seeing that we have a really profound impact on CRP, even in unstimulated, you know, patients, is telling us that our pathway engagement is really robust. And, you know, if you think about STAT3 outside of oncology for a second, where we've shown preclinically really strong anti-inflammatory effect, seeing that we have a robust effect on CRP, which is comparable to some active therapies, you know, makes us feel good that this, you know, this pathway and this particular target has still a lot to give.
Yeah. And do you, for translating some of the oncology data, specifically the knockdown and the downstream pharmacodynamic markers, for translating that to immunology, do you have kind of a framework set up at this point?
Well, I mean, I think the way we're experiencing STAT3 degradation in cancer is, you know, first understanding PK and PD, which I would suggest and assume that is transferable. Understanding safety, although, as you know, it's difficult to tease out safety in these patient clinical trials, and also understanding impact on downstream biomarkers. So I would say the picture that we have in front of us is actually quite intriguing and, you know, has given us more confidence to think about, you know, STAT3 outside of oncology. Nothing is really transferable one-to-one, but I think the overall picture is quite promising.
Makes sense. And I know you've kind of laid out the ASH update before, but anything else, that you would wanna add, given that it's coming up very soon?
Yeah, I mean, you know, the abstract was, you know, limited to a different cutoff date, so had, you know, besides PK/PD, that we-- I don't believe we even quantified in the abstract, but obviously consistent with earlier disclosures, you know, had some early clinical antitumor data and, you know, at least there was one partial response in CTCL. I would say we expect to have more evaluable patients, and so hopefully more data to share.
Sounds good. Just a quick question on IRAK4. I mean, you, you've laid out the atopic derm and the HS trial designs in a lot of detail, so probably won't go into that. But I was just wondering, are you working on any novel scaffolds for the IRAK4 target?
you mean novel-
Novel degraders.
... molecules, degraders?
Yeah, to kinda tune out some of the minor hERG liability.
Yeah. So, you know, as everybody knows, this program is in collaboration with Sanofi. We've said in the past that, you know, this program might include follow-up molecules, so we're not disclosing anything about that yet, but this is work that has been ongoing, and so it's still something we're working on.
Yeah, that makes sense. Maybe we can just kinda wrap up by reminding us on your cash balance and runway, and, just kinda laying out the catalyst, you know, in addition to ASH, but what we should expect for your R&D day for immunology.
Yeah, I mean, we, we have about $435 million as of Q3. We have had one milestone and an upcoming milestone coming in, that they are not part of that cash number. The cash will get us into the first half of 2026, which will allow us to obviously, you know, go through the ASH data, more STAT3 data next year, as well as MDM2 broad data that we discussed earlier today. We'll have the IRAK4 phase II data in both HS and AD in the first half of 2025. So roughly a year, roughly a year before, let's say, our cash runway ends. And, you know, as, as I mentioned, we have exciting programs that we're disclosing in the R&D day, and those are both funded and ideally generating early clinical data within this cash runway.
So there will be a lot to disclose in the next few years, and a lot of exciting new degrader data.
Sounds great, right on time. Thank you so much for joining us, Nello.
Thank you.