Good morning, everyone. Thank you for joining the H.C. Wainwright 26th Annual Global Investment Conference. My name is Li Chen. I'm an Equity Research Associate. This morning, I would like to welcome our first speaker, Jared Gollob, CMO of Kymera Therapeutics, a clinical-stage biotech company developing targeted protein degraders. Jared, please go ahead.
Great. Good morning, everybody. I am happy to provide an overview of Kymera and our pipeline. That's going to include really where we've been and where we're going, with a focus in particular on our STAT6 program, which is entering the clinic shortly. I'll also provide, you know, some information on what to expect in the clinic from Kymera over the next six to 12 months. Kymera, we really see ourselves as a leader in the field of targeted protein degradation, really, you know, by virtue of the fact that we have, I think, fairly aggressively advanced, you know, multiple sort of high-value degrader programs into the clinic, going after undrugged targets.
And we've evolved what we believe is a formidable drug discovery engine that's allowed us to more rapidly and efficiently, you know, prosecute high-priority targets. And importantly, we've also, I think, been successful in our execution in the clinic. We were founded just in 2016, but really over the past, I'd say, three and a half years, we've moved now four first-in-class programs into the clinic in both immunology and oncology. And in fact, our immunology program was really the first targeted protein degradation immunology program to go into the clinic. And I think importantly, we've now shown clinical translation of degradation and safety across all four of those programs. And so I think with all of this, we've now, I think, yielded extensive validation of our target selection, you know, in our molecular design.
I think, you know, given our discovery engine and our success in the clinic, you know, I think we are expecting to move at least one to two new programs into the clinic each year over the coming years. I think what's also important is that we're well-capitalized. We currently have around $930 million in cash and a runway that takes us into the middle of 2027. This really allows us to move through multiple key inflection points in the clinic and to move multiple additional discovery programs into the clinic over the coming years. I think our success really all begins with target selection strategy, and this slide really lays out, you know, how we go about focusing on what we call first or best-in-class opportunities.
And I think it all begins with the target themselves. And our focus is really going after undrugged or inadequately drugged targets. So the undrugged targets, typically for us, are transcription factors, and the inadequately drugged targets are often multifunctional proteins that have key scaffolding functions that can only be addressed using degraders. It's important for us that those target proteins lie within pathways that have very strong clinical and genetic validation already. We really want to take as little risk as possible on the biology side by choosing these sorts of pathways. And I think it's also important for us to always be able to show the degrader advantage over small molecule inhibitors as early as possible in development. So we always choose our pathways and our targets with that goal in mind as well.
And I think importantly, especially, which is exemplified with our pivot toward immunology recently, that we're very interested in going after large clinical and commercial opportunities where there's a high unmet need and where we think there really is substantial value creation using oral degraders in particular. So I mentioned earlier, you know, our translation from preclinical to the clinical side of things. And I think that's really important, you know, to really show that we've done this across our four programs that have gone to the clinic. And by translation, I'm talking about translating preclinical pharmacology, so understanding PK/PD relationship, translating safety, and translating efficacy from the preclinical models into the clinic.
We've done this for IRAK4, and on the top left, you can see that in the clinic, we've shown very robust knockdown of IRAK4 in blood and skin, including in skin lesions in patients with diseases. We've shown improvement in skin lesions and symptoms in hidradenitis suppurativa and atopic dermatitis patients, and that's now led us into phase II trials that Sanofi is running. For the IRAK4/IMiD program, we actually showed for the first time that a single degrader could degrade three different targets in tumor and blood, and we did that for these three targets, the IRAK4 and the IMiD substrates, Ikaros and Aiolos. And for STAT3 and MDM2, we've shown that we can strongly hit the target, block the pathway.
We can do it at doses that are safe and well-tolerated, and we've shown clinical proof of concept across both of these programs, with major responses in both liquid and solid tumors. So when we look at this high fidelity of clinical translation, the reason for pointing this out is that when you look at our current pipeline of programs about to move into the clinic, like STAT6 and TYK2, and you ask yourselves: "What's the probability of success here?" We think we can point to these four prior precedents of high-fidelity translation from preclinical to clinical, which gives us a high probability of success of our future programs, including STAT6 and TYK2, of translating in the clinic, as these prior programs have also translated.
So this is a snapshot of our pipeline, which, as you can see, is a mix of both, immunology and oncology programs, some of which are already in the clinic, and some of which are going to be entering the clinic, shortly, this year or next year. You know, we announced earlier this year, two new programs, STAT6 and TYK2, and this represented for us a pivot, toward a greater emphasis on immunology. You know, and the rationale for that pivot was in part because of the success we were seeing with our IRAK4/KT-474 program of showing clinical proof of concept even in phase I.
And that led to a recent positive development, you know, with Sanofi deciding to expand the proof of concept phase IIs into dose-ranging finding phase IIs, which allow us to go with just one step toward eventually pivotal registration phase III studies, you know, with these expanded phase II studies. And so that represents a real plus for the program, and that decision was based on a positive interim analysis of both safety and efficacy. The other rationale for the pivot is really our strong conviction that degraders against targets like STAT6 and TYK2 can truly reach the safety and activity of injectable biologics, and therefore, can be transformative in the various diseases where we intend to develop these drugs.
KT-621, you know, we have spoken of that drug as a so-called Dupixent in a pill, and here I think we can be transformative in the field of Th2 inflammation across multiple different diseases with an oral degrader. That program is slated to start in the clinic in the very near future. KT-294 is our TYK2 program, which we believe is the only program, you know, capable of recapitulating or phenocopying the TYK2 loss of function phenotype, and therefore can be a transformative program in diseases that are driven by IL-12, IL-23, and type I interferon, and we believe can truly differentiate this program in terms of being able to attain biologic activity, whereas small molecule inhibitors of TYK2 have lacked in that respect.
And then finally, you know, in our oncology program, you know, we're actually pleased with the progress we've made across both of these programs, STAT3 and MDM2. As I alluded to earlier, both of these programs have been dose-escalating. Both of these programs have shown strong target engagement and pathway inhibition, at doses that are safe and well-tolerated, and both programs have now shown clinical activity across both solid and liquid tumors. And we've completed dose escalation in STAT3. We're continuing to enroll Hodgkin's patients and intend to provide an update later in this year. MDM2 is still dose-escalating, and once dose escalation is completed across liquid and solid tumor arms, which may be later this year or early next year, we'll plan on providing an update there as well.
You know, with regard to our oral, our immunology pipeline, we truly believe that based on what we have now and what's coming right behind this in our discovery pipeline, we truly think we can have the best in industry oral immunology pipeline. So what's the opportunity in immunology that underlies in part our pivot to immunology? The opportunity is really quite vast, not just in classic immunology indications, but also in various indications, be they oncology or CNS, that also have immunoinflammatory mechanisms that are contributing to the pathophysiology. I mean, this is an enormous market. We're talking about a potential $250 billion worldwide market spanning multiple different therapeutic areas, and the issue here is that this market has truly been dominated by injectable biologics, which have been largely injectable monoclonal antibodies, you know, which have been quite effective.
However, you know, these injectables do limit access, and while there has been attempts, you know, to bring oral drugs into this space, the challenge here has been to develop oral small molecules using ligands against difficult-to-drug targets. It's been hard to find those ligands. It's also been very difficult to develop oral drugs that have the same activity and safety as injectable biologics, and this is the reason why the injectables continue to dominate. You know, so why do we think that, you know, small molecule oral degraders in immunology can really change the treatment paradigm here? As I mentioned, these injectable biologics have truly revolutionized, you know, the immunology field. These drugs are clearly benefiting multiple patients to a larger extent than any other drugs previously, and importantly, these injectables have validated key pathways in immunology.
They've validated IL-17, IL-23. Dupixent has validated IL-4, IL-13. So this validation, this clinical validation has been key, as well as the actual clinical success of these programs. However, the problem here remains that these are injectables, and because these are injectables, there have been problems with limitations of access. For example, with Dupixent in AD, for example, only about 10% of the millions of patients who could get this drug actually do get the drug. And that's because patients are reluctant to take injectables, clinicians are reluctant to give injectables in some circumstances, and payers have many, many hoops you have to go through before you can actually get to an injectable. It's also true that many patients who are already on injectable biologics would rather switch to orals if they had that option.
So the potential solution here is to develop oral small molecules against these same pathways. The problem has been that these are limited in both their safety and their activity. I think, deucravacitinib, you know, is one example. Sotyktu , which is an oral TYK2 molecule, which does have activity, but that activity clearly lags behind, the activity of the injectable biologics. And therefore, in some ways, having to take an oral small molecule inhibitor becomes a compromise. You're compromising either efficacy and/or safety. And so we believe that oral degraders, you know, would not be a compromise. We believe that this is the only approach, the only oral small molecule approach, that has the pharmacology, has the potency, has the selectivity, that can block these validated pathways to the same extent as injectable biologics.
If that really is eventually realized in the clinic, these can truly be transformative and change the entire treatment paradigm, you know, for these large, immunology inflammatory indications. With that as a prelude, I'm going to turn now to talking about our STAT6 degrader program, our first-in-class oral STAT6 degrader program. Why is there interest in STAT6, and why has there been interest in STAT6 for over a decade? The reason is that it's known that the IL-4 and IL-13 pathways drive Th2 inflammation and all the different manifestations of Th2 inflammation. There's been exceptional clinical validation of these two pathways with drugs like Dupixent, which is a monoclonal antibody targeting IL-4 receptor alpha.
So this clinical validation has led to a large amount of interest in trying to find alternate ways to drug these two pathways using oral small molecules. The challenge here has been, you know, to develop, you know, the right oral small molecule with the right pharmacology. The key target of interest here, and this has been of great interest to both large pharma and biotech over the past 10 years, has been STAT6. That's because STAT6 is the obligate transcription factor for IL-4 and IL-13. It is highly selective for IL-4 and IL-13, and it is required for signaling through IL-4 and IL-13. Human genetics have shown that activating mutations in STAT6 lead to Th2 inflammatory diseases, and in mice, STAT6 knockout mice actually are healthy and fertile with no phenotype.
So this tells us, through these, you know, human genetics, that STAT6 is the target of choice and that it can be safely knocked down. However, the issue here has been trying to develop ligands to STAT6, and even with ligands, trying to develop small molecules that can actually 24/7 block STAT6 and therefore block the pathway to the same extent as biologics. And we believe the only modality that can do this are degraders. So if an oral STAT6 degrader can truly block the IL-4, IL-13 pathway to the same extent as, say, dupilumab, this can transform the treatment paradigm for all these different indications that have already been de-risked by dupilumab. You know, these, you know, indications amount to more than 150 million patients worldwide.
These include large indications like atopic dermatitis, asthma, and COPD, as well as smaller indications, like EoE and, prurigo nodularis, and even indications that aren't even shown here yet, that Dupixent hasn't addressed, like food allergies, which could be an enormous space, that we could penetrate. Not only going into these same spaces, but getting to younger patients earlier, you know, especially in diseases like AD and asthma and EoE, where children and infants are suffering from these diseases. You know, oral alternatives can be quite attractive and quite a effective way to get to these populations earlier than one could with injectable biologics. So what's the advantage of having a STAT6 degrader? You've probably heard that there are companies looking to develop inhibitors to STAT6, small molecule inhibitors.
You know, we at Kymera are in the lead in this space with our STAT6 degrader that's about to go into the clinic. The limitation of small molecule inhibitors of STAT6 not only are usually selectivity and potency, but also because these are occupancy-based approaches, they're unlikely to give 24/7 , round-the-clock inhibition of that target. And if you can't have 24/7 , round-the-clock inhibition, you're never going to be able to block that pathway to the same extent as an injectable biologic, and this is going to become, you know, fall into the same category as Sotyktu, where you'll have activity against the pathway, but it'll never match the activity of biologics. We believe that our STAT6 degrader will be able to match the activity of biologics and be superior to any small molecule approach.
So turning to our actual degrader, KT-621, is really one of the best, if not the best, degrader that we've made at Kymera, and we have made thousands, if not tens of thousands of degraders over the past, eight years. If you look at the potency of this degrader, this is a, picomolar potency degrader, you know, low double-digit picomolar. If you look across all the different disease-relevant, cell subtypes in the blood, in the epithelium, in skin and lung, you know, in smooth muscle, in the lung and the GI tract, you see the same, you know, potent degradation of the target, where we essentially, are able to completely eliminate STAT6, with, incredible picomolar potency. Our degrader is also exquisitely selective. This is a proteomics plot looking at over 10,000 different proteins in the proteome.
The only protein that we degrade is STAT6. We don't touch any of the other STATs or any other proteins, which tells us that we can push the dose to fully degrade this target without worrying about off-target effects that can limit safety. Not only do we not degrade STAT6, but we also do not functionally inhibit any of the other STATs, which is shown on this slide. We don't affect STAT1, 2, 3, 4, or 5 functionally, so in addition to not degrading the target, even if we're binding to the target, we're not affecting its function whatsoever. Again, which tells us that we're highly selective and to be able to avoid any off-target effects that could be problematic.
What's also important is that not only can we degrade the target, but we can functionally inhibit the downstream pathways that are relevant for a Th2 biology standpoint for both IL-4 and IL-13. And we show that not only can we do it to the same extent as a saturating dose of dupilumab, but we're actually more potent than dupilumab. We're up to tenfold or even more than tenfold potent than dupilumab. This is almost really never been seen with a small molecule. To have a small molecule that is not only as active as a monoclonal antibody, but actually tenfold more potent than an antibody is really unheard of in the field. Now, what's important is that in vivo, we can strongly degrade STAT6, and we can do this 24/7 . So here we're looking at the dog.
We're looking after seven days of daily oral dosing with our drug, and we're looking 24 hours after the last dose. So this is the trough level of degradation. And you can see that at relatively low doses, we're able to almost completely obliterate STAT6, knocking it down by 94%-98%. And these are trough levels. So this is telling us that round the clock, we're degrading IRAK4 by greater than 95%, with relatively low oral daily doses. We've also shown this in non-human primates. This is with 14 days of dosing in a non-GLP tox study using a low dose of 10 mg / kg, which is already giving us exposures that are 40-fold above the clinically efficacious dose. And here you can see we're essentially eliminating STAT6 from multiple different tissues and doing this without any adverse events.
You know, we've now completed all of our IND-enabling studies for this drug, including four-week tox studies in non-human primates and rats. We have seen no adverse events, no gross or microscopic histopathologic changes. Again, in line with what we believe is that STAT6 is a target that we can knock down safely based on what I already mentioned from human genetics. And I think very importantly, we've shown in vivo that we have activity that is at least comparable to dupilumab. These two workhorse models that I'm gonna show you, one is in AD and one is in asthma, have been used by dupilumab to show activity there. And as you know, these have translated into exceptional activity for dupilumab in AD and in asthma and COPD.
Here we're looking at increasing doses of our degrader, KT-621, and we're dosing here for eleven days and comparing this to the saturating clinical dose of dupilumab, given in the same model. And you can see that across all doses of 621, we're getting substantial reduction of IgE, with knockdown of STAT6 ranging from 70% all the way up to 90%, measuring STAT6 degradation in the spleen. And that's associated on the right with profound reduction of serum IgE. And you can see that at doses of our drug, where we're getting 85%-90% degradation of STAT6, we are completely suppressing IgE to the same level as the saturating dose of dupilumab. And likewise, in this house dust mite asthma model, we show something similar. Here we're looking again across these same three doses of our degrader.
We're comparing to dupilumab, and we're showing suppression of relevant Th2 cytokines, of relevant Th2 inflammatory infiltrates to the same extent as dupilumab, especially when we're knocking down STAT6 by at least 90%. We've even shown impact on histology, where we're able to prevent this goblet cell metaplasia in the lung, again, with doses of 621 that are giving us at least 90% degradation. This is telling us that our goal here should be degradation of STAT6 by at least 96%, by at least 90%, excuse me, which can then essentially potentially mirror the activity of dupilumab, full saturating doses of dupilumab in the clinic. In summary, I've gone through much of what is on the slide already. I just want to focus on the right side of the slide.
You know, we have a degrader that has picomolar potency, that shows full functional inhibition of the IL-4, IL-13 pathway with 90% or greater degradation. We've shown robust activity in the same workhorse models of AD and asthma, where dupilumab has shown activity, which gives us confidence that this drug has the potential to be a dupilumab in a pill. We've completed all of our IND-enabling studies. We've not seen any safety signals whatsoever, with high doses that are giving us complete degradation of STAT6, and we now expect to be in the clinic shortly, and my last slide here will just be to reiterate again what to expect over the next six to twelve months in the clinic.
For IRAK4, as I mentioned, we've recently expanded the phase II studies to accelerate overall development, and we expect the new design of these phase II studies, including additional doses and additional patients, to be posted on clinicaltrials.gov in the coming weeks to month. So you'll see more details on what those trials look like. But we're very excited by Sanofi's commitment to both of these programs and the potential for IRAK4 in this space. 621 is entering the clinic soon, imminently. And you know, this is gonna be a healthy volunteer, SAD/MAD study. The primary objective is gonna be to show in this study that we can fully degrade STAT6 in blood and skin by over 90% at doses that are safe and well-tolerated.
If we demonstrate that, that will immensely de-risk this program and increase the probability of success once we move into patients. And then KT-294 is slated to enter the clinic in the first half of next year, and for us to have a data readout in the second half of the year. And then lastly, for the oncology programs, as I mentioned, these are continuing with dose escalation, and we expect readouts later this year for KT-333, probably early next year for MDM2, where we can provide further guidance on direction and next steps for those programs. And with that, I will stop. Thank you.