Welcome back to the 44th Annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here at TD Cowen. Really pleased for the next session to have Kymera and their CEO, Nello Mainolfi, here for a little chat about their programs. Nello, maybe to start off, just for people who may be a little bit less familiar and less in the weeds on the story, can you maybe just give a kind of high-level update of Kymera and just what layout, kind of what you think are the key milestones over the next 12, 24 months or so?
Yeah. So thanks for the invitation. I know we're enjoying some 80s rock music, but now you got to listen to me. So again, thanks for having us. It's always good to have a conference in town, actually, when we don't have to travel. So Kymera, just to give a really brief overview, Kymera was founded just about almost eight years ago with the goal of building a fully integrated company based on a novel drug modality called targeted protein degradation. Targeted protein degradation, at a really high level, is a small molecule-based modality that allows you to degrade and so remove disease-causing protein from the cell in an almost genetic-like knockdown manner, again, by using a small molecule. So these small molecules are catalytic, can be dosed orally, it can have profound impact on pharmacology and obviously on diseases of patients.
We have focused in immunology and oncology in the past few years since we became, I would say, since we also became a public company. We have focused on targets that have been difficult to drug or totally undrugged within pathways that have been validated by other agents where we believe a protein degrader will allow you to have a best-in-pathway, a best-in-class drug. So we have three programs in clinical development, two programs about to go into clinical development. Our more advanced program is our KT-474 degrader. This is an IRAK4 degrader for a broad variety of immune-inflammatory diseases. We're in phase II in both HS, hidradenitis suppurativa, and AD, atopic dermatitis.
These are programs that we have partnered with Sanofi, and Sanofi is currently running those phase II studies with the expectations of phase II data in both HS and AD in the first half of 2025, so roughly a year from today. We have two oncology programs also in the clinic. We have a KT-333, which is a STAT3 degrader. This is a first-in-class agent against STAT3 that specifically and selectively removes these transcription factors in a cell-agnostic manner, meaning degrades STAT3 in both cancer cells and immune cells. This target has broad applicability. We're exploring it now in hematological malignancies and solid tumors in phase I dose escalation. We expect to report broad phase I data this year at medical conferences. We have already shown proof of concept in this program in heme indications that we reported at ASH in 2023. We have another oncology program, KT-253.
This is an MDM2 degrader. This has an opportunity to really target the MDM2 p53 axis in p53 wild-type tumors. This molecule is designed to degrade extremely quickly, MDM2, drive cell into apoptosis, and we've seen to be differentially driving apoptosis than traditional small molecule inhibitors. We have reported really a handful of patients' worth of data in November with already first patient on study having a prolonged partial response. We're going to share more data of that phase I study later this year. Then we have two immunology programs, a STAT6 degrader, which we believe will be able to demonstrate biologics-like activity in the clinic. This is in the dupilumab pathway that we're initiating phase I later in 2024. Then we have a TYK2 degrader that will start phase I in the first half of 2025.
Maybe I spoke for too long, but that's a brief overview of the company, of the programs, and maybe happy to spend more time.
Yeah.
Are we supposed to be separated by a chair or no?
Yeah. Well, I bite sometimes, so. But maybe we'll start just because I think in part because they're the newly unveiled assets, it does seem to be some of the larger portion of investor conversations I have, at least. We'll start with the new immuno assets that were kind of unveiled back in January, the STAT6. Maybe we'll start with STAT6 and then we'll get to TYK2. Just, can you remind people STAT6, why that is, this is not something that we've seen a lot of autoimmune programs targeting before. Just why this target, why degradation is really the key way to get to it.
So KT-621, which is a program that right now is in IND-enabling studies, which again, as I mentioned, we plan, assuming success, initiate phase I study later in 2024. KT-621 is the first agent against STAT6 and obviously is also the first STAT6 degrader in development. So why STAT6? So again, looking at the philosophy of the company, we've always thought about what are those pathways that have a high degree of validation? What are those mechanisms that protein degradation can unlock a whole new value for patients? And what are those targets, again, that only a degrader mechanism can deliver full value? And so starting from the pathway, this is STAT6 is the selective specific transcription factor of the IL-4/IL-13 pathway. So IL-4/IL-13 pathway is one of the most well-validated pathways in Th2 inflammation.
dupilumab, commercialized as Dupixent, is the largest drug and will probably become the largest drug in immunology in a few years and is a drug that has changed how Th2 inflammation is treated. This is atopic dermatitis. This is asthma. Hopefully, soon enough, it will be COPD. It is prurigo nodularis. Is it chronic rhinitis? Is it EoE? It's across derm, respiratory, as well as GI, Th2-driven inflammation. One of the most well-validated pathways out there and what we thought was that what would really transform even more Th2 inflammation is to bring forth an oral therapy that will match dupilumab-like activity, but again, have the convenience and the ease of development of a small molecule oral drug. That's what a STAT6 degrader hopefully will be. Preclinically, we've already demonstrated it can be. This is a molecule that is highly selective for STAT6.
STAT6, as I mentioned, is the obligate transcription factor of IL-4 receptor signaling and is difficult to drug with other modalities being a transcription factor. We're able to target it with, as I said, with an oral degrader. The opportunity here is that while, again, as I mentioned, Dupixent is an exceptionally successful drug, it really targets a small percentage of that population. I think from the last thing that I've heard, Dupixent has been dosed to 800,000-900,000 patients. There is about 150 million patients in the world with Th2 inflammation, diseases that I've told you about. So our goal is really to enable a whole new generation of patients to be served by a small molecule oral drug that has the activity of a biologics, but the convenience and the accessibility of a small molecule oral drug.
Based on the preclinical data, I mean, I guess being downstream and maybe a degradation, we often think of it as a little bit more complete suppression of pathways than some of the other mechanisms or potentially gets there. Is there a reason to believe this could not just be equivalent to Dupi, but actually be superior from an efficacy perspective, or is it really just about matching the?
No, it's a great question, Marc. And I love how we try to move the goalpost to always harder. But I think it's extremely difficult if you look at the landscape to have small molecules that can match biologics activity. And the reason why we say that a degrader can is because, as you were saying, as you know the space really well, degraders can block the pathways with a saturating ability like a biologics because they're a catalytic mechanism. There is the fact that protein is removed completely. You need to wait for time to be resynthesized. So we can basically match the saturation that a small molecule can't because it's a stoichiometric mechanism and the PK/PD relationship is complicated to match to one of a biologics.
What I will say that biologically, when you use a saturating dose of dupilumab, meaning you block IL-4 receptor alpha signaling completely, if you remove STAT6 completely, biologically, you're doing the same thing. Basically, what I meant by saying that is that you're able to block the pathway downstream signaling the same way. So it's really hard for us to say that biologically we can be superior than Dupixent or dupilumab. I think you can potentially think that the small molecule and we're talking about a small molecule of slightly over the traditional molecular weight size might have a distribution profile in tissues and organs and cell types that might be better than a biologics. And maybe that will drive a different type of activity. But I think right now it's postulations. Right now, what we're saying is we have a drug that blocks this pathway completely.
We've shown preclinically in terms of potency, we're superior to dupilumab. In terms of in vivo activity, we've shown that we can hit those biomarkers at least as well, if not better. And now it's really going into the clinic and demonstrate the same in healthy volunteers and then eventually, hopefully, clinical activity in patients. And then at that time, we can start teasing out the levels and the depth of clinical activity.
Okay. Are there to that point of maybe distribution, is there any sort of indication that would kind of be the test case for that in your view of whether the distribution potential is playing out?
Well, I mean, I think the beauty about protein degradation that we at Kymera exploit as much as possible is the fact that you can monitor the most proximal biomarker everywhere, especially preclinically, everywhere in tissues and organs of animals. So we've demonstrated that a dose that degrades 98%, 96%, 99% of STAT6 in blood, that's the same in spleen, that's the same in lungs, that's the same in GI. So we know there are drug distributes equally across all relevant tissues. In reality, with small molecules or antibodies, you really don't have proximal biomarkers. And so you're looking at distal downstream biomarkers, and those are not also relevant sometimes in particular tissues. So it's difficult to know, to be honest, what is the distribution and the activity in particular subsets of tissues of other drugs. We know we have it, and we know that we maximize pharmacology.
Now, again, as I say, I think to compare, we'll have to look at clinical data.
As you get into the clinic, that is, as you start dosing, the goal is essentially to get as close as you possibly can to 100% degradation at 24 hours a day, seven days a week. Is that the profile you're looking at?
Yeah. I mean, I think as we've done with IRAK4 in our healthy volunteer study, we like to saturate degradation. I think it's important to make sure that we demonstrate that the molecule is able to do that. And then in those ranging studies, we might want to ask the question, is maximal degradation versus 90% versus 80% different? We've seen preclinically that 90% degradation in preclinical models of STAT6 gave equal or superior impact on downstream Th2 biomarkers in, let's say, in vivo asthma model than a saturating dose of dupilumab. So we know that around 90% is sufficient. But I think we want to ask the question, what is saturating dose, maybe, let's say, versus a 90% dose versus even a lower dose? What does that do to different diseases?
Okay. And I think when you were unveiling these, you did discuss that you think there are biomarkers that not just the obviously, you look at degradation STAT6, but biomarkers even in healthy volunteers that may be moving to tell you the broader pathway engagement. Just, can you review that? What are those relevant biomarkers?
Yeah. I mean, I think if you follow, again, dupilumab and other drugs in this pathway that have been developed more recently, you see that in healthy volunteers, some Th2 biomarkers can be modulated by impacting this pathway. I think the most common ones are Ig and TARC. The modulation is not as robust as in patients. I think if you look at the data for, let's say, TARC, it's somewhere in the 20%, 25%, 30% and Ig probably the same 18%-25%. And so I think it's a qualitative assessment of pathway engagement. But I think as it's tied to target degradation, I think it's an important initial de-risking of the molecule is doing what it's supposed to do. Then as you go in patients, actually, the data that has been generated is extremely robust.
I mean, if you look at these biomarkers in patient, you can get really, really strong inhibition. There are other biomarkers, periostin and others that you can monitor. In skin of AD patients, there is a very well signature of dupilumab of, let's say, Th2 inflammation that you can monitor in skin even after a few doses, a few days of dosing. So we're fortunate we have a well-defined blueprint of what we want to need to show to demonstrate that we're blocking this pathway in a clinically meaningful way, even before we actually run in these fully fleshed out phase II studies.
Okay. And well, hopefully, you establish all that in the healthy volunteers and the initial kind of phase I, potentially phase I experience in patients. But Dupixent has a very broad label, but there's also additional indications in allergy and immunology that the pathway makes sense in. Just how do you think about prioritizing indications and going kind of one option going for everywhere Dupixent's already approved and a very big and established drug and proven a huge market versus kind of trying to find these other opportunities where maybe Dupixent isn't even quite there yet?
Well, I think I feel it's our responsibility to provide patients. Again, we're talking about more than 100 million patients with a convenient, accessible oral therapy. I don't think it would be responsible for us not to go into the indications where we expect the drug to work first. And so we know that drugs that block this pathway work really well in ADs, in asthma, in COPD, and others that I mentioned. And we have to be there, again, to provide patients with potentially different, more accessible options where you don't need syringes, fridges, and other challenges. But then it's also our responsibilities to go beyond that. And we are doing research, preclinical research as we speak, to look beyond those indications. But I think we need to start where we know the drug is expected to work.
Okay. Maybe turning to TYK2 quickly, just there may be the rationale for why a degrader? Because I think we've seen efficacy data. I mean, obviously, there's an approved agent and so TYK2, but even some efficacy data from other ones that there's certainly a lot of efficacy on the table with this pathway, but it also hasn't quite matched some of the other agents, at least in psoriasis.
Yeah. I mean, I think that's what it's all about, right? I think so, TYK2 is one of the most elegant stories of human genetics that has ever been prosecuted. We need to give BMS a lot of credit for being the company first to actually take on that challenge of looking at human genetics mutations and loss of function and knowing that if you have those particular genetics, you're protected against specific diseases. They developed this molecule that tried to show that. In fact, it has shown that. The reality is that if you look at full loss of function, the actual profile is quite different than the partial loss of function or particular mutational loss of functions that small molecules are more closer to replicate.
I think what we're saying is that small-molecule allosteric inhibitors have shown that this target is relevant in psoriasis. I think there is exciting data in lupus. I think IBD, the question is still out there, at least with TYK2, it didn't work. I think there is a specific reason for that, we believe. But there's clearly a role for this mechanism. We just don't believe that any drug that right now is in clinical development is addressing this mechanism fully. And the only way to do it fully is by removing the protein and replicating the full loss of function genetic profile. And that's what we want to do with our degrader.
Okay. Maybe just looking across the TYK2, the STAT6, obviously, the preclinical development, the phase I, well within the capabilities of a biotech. And maybe one or two of these indications you could even do yourself. But the development program can get quite large, quite fast if you really want to follow the entire Dupixent label or all these places TYK2 has been proven to work or believe that it could work. How are you approaching it from a BD perspective? Is something looking kind of like the 474 partnership with Sanofi, how we should look at this? Obviously, it'll be at a somewhat later stage or take this to registration. Just how are you approaching it?
Yeah. I mean, I would start with saying our company strategy, I've been saying it for eight years, is we feel like it is our, again, I'll say it again, responsibility to build an integrated company because we have never seen new modalities being developed outside of committed biotechs. And so we want to go all the way with protein degraders and build a real independent global company. Many companies have done this very successfully. I mean, not many, but a few have done it successfully. We want to be one of those companies. And so we need to be prepared to take these programs all the way. Now, it's going to be challenging and maybe naive to expect that we're going to be doing this for all the programs on our pipeline. But we are committed to building capabilities to generate real value for these programs.
Then I think it's probable that for some of these programs, there'll be a strong partnership later in clinical development or more likely commercially to make sure that we maximize the commercial value of these drugs. Then eventually, we'll be able to do all of that on our own too. But I think it'd be maybe naive to expect that our first internal approved program in an indication that has 100+ million patients will be able to commercialize all on our own all over the world. That might be a bit of a stretch.
Okay. And before we leave immunology, you do have, I alluded to it a second ago, but 474, that is with Sanofi. Of course, Sanofi will have their own decision as we get phase II data early next year. That's independent of you and your views. But you will then have your own opt-in decision if they decide to move forward. What are you looking to see to want to participate?
Yeah. I mean, I think the opportunity with this drug is to have a broad anti-inflammatory agent that actually can go across kind of Th1, Th17, Th2 in a different way than STAT6 and TYK2, but in a meaningful way. And I think the profile of this drug could be an active, well-tolerated oral option that should be considered early in the treatment paradigms in a broad variety of indications. So what we're looking for is to demonstrate in a clear manner. As you know, we run a non-controlled small study, which was, we believe, positive, but difficult to fully appreciate the clinical impact of this drug. So for us, it's really demonstrating clinical activity in HS and AD. And I think if we see that with a good safety profile, we believe this drug has the potential to be a really big drug in immunology.
Given that actually the opt-in from Kymera to a 50/50 co-development, co-commercialization would only require us quote sign for people not on video, only require us financial participation, but not operational one. I think our models tell us that in the case of an active drug, it should be a reasonable path for us to opt-in. But we'll have to look at the data. And then remember, the decision will be before our first phase III study. Obviously, after phase II, but Sanofi will have to be planning a phase III study for that trigger to start the clock.
Okay. And now maybe turning quickly to oncology, we'll start with the MDM2. We can summarize what you've managed to accomplish so far in the data that you did. You presented some data late last year and maybe set the stage for how big of an update we should expect later in the year.
Yeah. So we started this program with the same, again, same philosophy, big, big, big pathway, p53 wild-type tumor, clearly not well-drugged by small molecule inhibitors. Our biological case was we remove the protein, we drive cell to apoptosis, we drive healthy cells to recovery and not to apoptosis. And that should drive a meaningful biological and clinical difference. And so that's what we're exploring in the clinic. Preclinically, the data is we believe the data are compelling. Early clinical data, we showed really, I think, two cohorts' worth of data in our quarterly call in November. First patient on study had a prolonged partial response without any signs of your typical MDM2 heme tox. And so it was telling us that we were on the right track. Since then, we've initiated an AML cohort, AML-ALL cohort together with the solid tumor lymphoma cohort.
We expect this year to be able to tell the story of our phase I dose escalation study, what we've been able to learn, and more importantly, where we're going. It might be in one or two disclosures in medical meetings, depending on the type of meetings and the type of data. But more importantly, I think together with the clinical data, we're really keen to being able to tie our clinical data with a sensitivity biomarker plan that will allow us to develop MDM2 degraders in a, let's say, targeted manner. And that hopefully will be the story of 2024 for MDM2.
And with that update from the kind of and where we're being able to lay out the next steps, is that you will maybe have some anecdotal activity in places, or is it you expect this data set to be large enough that you can really truly have proof of concept in lymphoma, but maybe not AML or vice versa or hopefully both?
I think our goal is to have proof of concept in enough patients across enough tumor types that will validate our sensitivity biomarker-driven development. So maybe in each tumor type, it might be difficult to say we've got six out of 10 of six different tumor types. There will be probably a lot of patients. I don't think we'll have enough of that. Hopefully it will be enough patients from enough tumor types that all fulfill this particular criteria that we build the confidence to say, look, the criteria for selectivity and sensitivity is being defined preclinically and already validated in our phase I study. Our phase I-B and beyond will be driven by this strategy.
In order to really move forward, do you need to be convinced the activity is enough that this could be a drug on its own go all the way as a single agent?
Yes.
Yeah. Okay.
Yes. I mean, as you know, all drugs are then combined, but we expect to see single agent activity.
But not just activity, but that there's a meaningful registrational path as a single agent.
Meaningful activity as single agent. Yeah.
Okay. And then maybe we'll go to STAT3 in the last minute or two that we have. So there, it's a little bit different, right? There isn't as much of a single agent expectation in at least parts of the development program. I guess how will you evaluate that? And I guess given that there are two different hypotheses, one for the niche single agent opportunity in some lymphomas and leukemias versus the larger solid tumor where there's less of it, do you have to validate that niche opportunity in order to move forward in the larger?
I mean, I think you want to know you have an active drug, right? I think so first, if we're talking about the heme opportunity, we've shown already in CTCL and Hodgkin's lymphoma, a small number of patients that we had some strong responses. And so what I would expect this year is to have more patients from those tumor types to actually get a sense of how active the drug is. And then what Marc you're referring to is the potential combo opportunity in solid tumor. I think it's really hard to say I have a combo opportunity in solid tumor, but I have no single agent activity in any tumor type. I think that'll be a difficult case to make to ourselves or anybody to advance the drug beyond phase I-A dose escalation.
So our base case is we have some strong measurable activity as a single agent in some tumor types. And then we continue to make the case for both in both preclinical and clinical that there is a place in solid tumors for this drug in combination. But I think, again, we expect single agent in heme to be part of that.
Okay. Unfortunately, that's all the time we have, so we're going to have to cut it off. But thanks a lot for joining, Nello, as well as everyone in the room or on the webcast.
Thank you. Thanks, Marc.