Good morning, everyone. Thank you for attending Jefferies Healthcare Conference. In this fireside chat session, we are so pleased to have Mr. Nello, CEO, and also Jared, the CMO from Kymera Therapeutics. Welcome both, and-
Thank you.
Thank you.
Maybe, before we get into the pipeline, maybe we can start talking about the technology differentiation in this very exciting protein degrader space.
Sure. So, thanks everybody for attending. Thanks for the invite. So just to tell you a bit more about Kymera. So, we started the company with the goal of building a fully integrated global biotech that will take targeted protein degradation as a founding technology to deliver a new generation of medicines. And in doing so, by going after target proteins that have not been drugged or drugged well before. And that is, I believe, the promise of this technology, is to be able to do things that other technologies can't. And so if you look at what we've publicly disclosed so far, you know, we've decided to focus in immunology and oncology, going after mostly scaffolding protein, multifunctional proteins, or transcription factors.
Both are classes of targets that cannot be drugged, at least not well, by existing modalities. The beauty about protein degradation is that allows you to affect protein in the whole body, so you're not limited by tissue types or organ types, and it's obviously a small molecule-based modality, so allows you to build drugs that can be dosed orally and reach systemic distribution in an effective manner. So we as of January we've talked about our enhanced focus in immunology with the promise of building a new generation of oral drugs with biologics-like activity.
So we've talked about on top of our IRAK4 program, which has been in the public domain for a few years. We talked about our STAT6 degrader that has promised to have Dupixent-like activity in the clinic, and our TYK2 degrader, which we believe will have opportunity to mimic or reach biologics-like activity in that space, IL-23, type I interferon, IL-12-like biologics. And then we have two oncology programs that we've shared data at ASCO recently, and we'll share data at EHA. Exciting activity and a great safety profile. So I'm sure we'll discuss them as we go through the Q&A.
Terrific. Given that you mentioned the very broad immunology and oncology pipeline, can you talk about your strategic consideration between these two? Whether you prioritize one over another?
Yeah. So what I will say is that, you know, our target selection is rooted into key principles that, you know, I've mentioned in the past: undrugged protein, in validated pathways with clear degrader rationale, and meaningful commercial opportunities. I would say that with the evolving healthcare landscape, both in terms of, pricing regulation as well as regulatory, evolution of how we think about, developing medicines, I think it is fair to say that, we're looking at the landscape, in oncology and immunology and in other diseases with the same, with the same view. Meaning that for us to, as a company that obviously is trying to create value for patients and for our shareholders, we look at, at opportunity set equally across the board.
So for us to invest in oncology, we need to find opportunities where there is a clear, meaningful opportunity to be best in class in that category, and also to have large, meaningful patient populations. So I think if you look at all the diseases with the same view, then I think it would be fair to say that the opportunity set in immunology is broader, and I think for some of the targets that we've chosen, really meaningful. And I think for us to continue to invest in oncology as we are, we'll have to meet the same bar. That's how I would like to say.
So maybe if you then summarize, I think it's easier to see a direct value-creating opportunities in immunology than it is in oncology these days. At least that's our view, but that doesn't mean that there aren't incredibly interesting opportunities in oncology also.
Excuse me. So the IRAK4 program is of great investor interest. It'll be exciting to actually look at the top line from both atopic dermatitis trial and also hidradenitis suppurativa HS trial next year in first half. But recently, a few IRAK4 inhibitors have been discontinued for similar indication. Can you talk about the evidence that the IRAK4 degrader can work better or differently?
Yeah. So we started this program in 2017, and the investment thesis in IRAK4 was that the IRAK4 target as a protein had been an interesting target in the biopharma industry for probably now 15-20 years almost. And the promise for the target was that it was downstream of a series of validated cytokines as well as receptors. So it's downstream of IL-1, IL-18, IL-33, IL-36, downstream of the TLR receptor. And drugs to those particular proteins have shown activity in a plethora of immune inflammatory diseases: HS, AD, asthma, macrophage activation syndrome, gout. And the promise was if you go after an intracellular target, you should be able to replicate the composite clinical activity of all these upstream biologics.
So the idea was, with the intracellular, IRAK4 agent, you should be able to be superior to the upstream individual biologics. Now, what we learned by then already was that targeting the kinase function of IRAK4 was and is insufficient to block the downstream signaling of this pathway. In fact, we know that, Pfizer, that had a small molecule program, showed some interesting data in RA, and then really generally negative data in HS. I think we've also seen Gilead pivoting from their small molecule kinase inhibitor to an investment in degraders. And then we've seen more recently, Bayer discontinuing that program. It's unclear why, but I think we assume that across the board, what we're seeing is the validation of our thesis, which is that inhibiting the kinase function of IRAK4 is insufficient.
If you look at all the preclinical data that we've shared, both in medical meetings, in publication, we had a Nature Medicine paper last year, as well as in investor events, we've shown that degrading IRAK4 and blocking both the kinase and scaffolding function is able to uniquely block the full signaling of the pathway, and kinase inhibition is insufficient. We've shown also in our phase I data, in HS and AD, given that it was a small study, also a small uncontrolled study, but we had some really exciting data, both in terms of pathway blockade, but also, in terms of, impacts on signs and symptoms of HS and AD. So I think that actually validates our thesis instead of impacting our thesis.
Super helpful. What would be your expectation on the data, and can you talk about the criteria that you use in deciding whether you would like to opt in?
Yeah. So, you know, I think maybe I'll let Jared comment on the expectation for data. But for us, there is this question that you're asking, which is, in the contract with our partner, Sanofi, we have an opportunity after phase II, but before phase III, to opt in and share 50/50 development and commercialization in the U.S. So it's actually a meaningful, we believe, value-creating opportunity. And, you know, our decision will be based on the totality of the data, obviously, and the opportunities that we have in front of us.
Given the potential breadth of opportunity that this drug could have, even beyond HS and AD, we believe that in the presence of encouraging data, you know, the probability of us opting in will be pretty high.
Great.
But, Jared, I don't know if you want to comment on the data itself.
Well, I think both of these studies in HS and AD, these are randomized, placebo-controlled phase II studies. You know, they're about 16 weeks in treatment duration in moderate to severe patients. I think our expectation is to be able to, number one, show safety relative to placebo in both the HS and AD studies, and then importantly, to show a treatment effect, you know, relative to placebo, you know, across both the primary and secondary endpoints. And both of these studies have endpoints that include measurements of skin lesions as well, you know, importantly, endpoints measuring symptoms, including pain for HS and itching or pruritus for AD.
Great. The competitive landscape of HS and AD is constantly evolving. How do you see your IRAK4 program will be positioned, especially as a oral option and specifically the disease severity and also the lines of therapy?
Yeah, I mean, you know, the, the, again, the investment thesis for us, for IRAK4, in a variety of immunoinflammatory diseases is that this particular pathway could be viewed as a broad anti-inflammatory agent, with a good safety profile. At least that's the expectation based on both human genetics as well as the data we've generated so far. And so, we believe that there are no small molecule oral drugs in these spaces that actually have both, a good activity and a good safety profile. So ideally, you know, it would be great to have this drug as first-line oral ahead of biologics. I would argue, you know, I don't expect that you'd have to have activity superior to biologics to be placed in that particular space.
But obviously, this is a decision that will be made, you know, eventually with and by Sanofi, and more importantly, after we've seen the actual data in larger and longer studies.
Based on biology, do you see potential of IRAK4 in other indications, and do you have a clinical plan go along with that?
Yeah, again, I cannot speak for Sanofi. They will be the one making final determinations on that. But I think just looking at the biology, we expect that an IRAK4 degrader should be active in other diseases where this pathway had activity. You can imagine asthma, COPD, IBD, lupus. And so I think the opportunities is broad. We know that you know there are discussions with our partner about going beyond HS and AD, and we'll let them decide when is the right time to publicly disclose that.
Terrific. And you presented a very impressive data for the STAT6 degrader recently, and would you highlight what is the most important preclinical data or clinical or human data evidence to support STAT6's potential?
... Well, you know, STAT6 is one of those amazing opportunity of going after an intracellular target that could replicate an extracellular receptor biology. So in this case, we know that IL-4 receptor alpha, which is targeted by dupilumab, marketed as Dupixent, has demonstrated impressive clinical activity and commercial traction in a wide variety of Th2-driven diseases like atopic dermatitis, like asthma. We've seen, you know, impactful clinical activity in COPD, in prurigo nodularis, in EoE, in chronic rhinosinusitis. So it's clearly, you know, hundreds of millions of patients we can say in the world that suffer from Th2 inflammation. And STAT6 is the selective transcription factor downstream of the IL-4 receptor alpha. In fact, when IL-4 bind to the receptor, STAT6 is recruited to that receptor.
So thanks to targeted protein degradation now, we can finally target this difficult-to-drug transcription factor with a binder and eventually through degradation. And so we believe, based on the data we've shown so far and the biology that we've studied, that a STAT6 degrader has the potential to have a dupilumab-like profile clinically, but being an oral daily pill, which we believe has the potential not only to obviously enter the market as a competitor to biologics, but actually believe has the potential to change treatment paradigms in many of these diseases, given that we have never witnessed, and obviously there is data that we will have to show to fulfill what I'm saying, but we've never seen in immunology or probably in any other disease area, an oral drug that has a profile of a biologics.
I think the potentials are vast. We are entering the clinic now, so, you know, there is a lot between what I'm saying and what we need to show, but obviously the premise and the promise are very exciting.
Will the data from a phase trial in next year provide a inflection point for the STAT6 program? What kind of a clinical data do you think will provide a proof of concept to de-risk the program?
Yeah, I'll let Jared maybe address this one.
Yeah, I mean, I think our current plan, you know, is to start off with a phase I study in healthy volunteers, probably at both a single and multiple ascending dose study. That would obviously be looking at safety with dose escalation, but also importantly, looking at target engagements as we can readily measure STAT6 in blood and skin, so looking at target degradation as a function of dose. Also, in healthy volunteers, we're actually able to also measure certain Th2 biomarkers in the blood, biomarkers like TARC and IgE, that have shown to be modulated in healthy volunteers with Dupixent, for example. Regeneron has shown that in their, in their publications. We think we have a unique opportunity in a phase I healthy volunteer study to show that as well, so that we're showing not only on target proof of mechanism, but also proof of biology.
So I think that, that's those are our expectations for what we can show in the phase I healthy volunteer study. You know, our aim, even though we haven't provided specific guidance yet as to design of the phase I healthy volunteer study, is to go fairly quickly from that, you know, into a patient study where we can provide, you know, further proof of mechanism and proof of concept, and further impact on a wider array of Th2 biomarkers in blood and potentially also in skin.
Would you plan to disclose indications to pursue along with the data update?
Yeah. So we, I think at this point, it's, it's early for us to talk about our clinical development plan. What I would say high level, given that this is a world probably in-- be even more a competitive space, but what I can say is our goal is to both maximize, you know, how much time or minimize time to registration, but at the same time, maximize the opportunity set. As you know, there are several indications where this drug could be active in, and given, the, the, what it takes for, for, for us to, being able to show success in these indications, there, there will be focus on likely parallel tracking, some of these large indications as we develop the drug.
We'll share more details there, but I think maximizing value means, you know, time to registration, but also breadth of development plans. Again, we'll show probably more next year.
On another very interesting target in immunology, TYK2, you also set a program to start in next year. Just curious, can you provide an overview of the data to date and the potential clinical profile, and then what additional work will need to be completed before you're able to move to the program into clinic?
Yeah, maybe I'll touch some of these. I'll let Jared comment on the clinical profile. So, again, this is another program that was started with the goal of, you know, really meeting a need. The need is having an oral drug in the IL-23, IL-12 type one interferon biology that can reach biologics-like activity. If you look at the drugs, Stelara and others, there is no small molecule oral drugs that can come close to the level of activity that we've seen with biologics. We know that TYK2 small molecule inhibitors are interesting drugs. Obviously, are drugs that have helped and will help patients, but are not able to block the pathway in the same way that a degrader, and the reason is very simple.
If you look at human genetics, the loss-of-function profile, and then you look at the catalytic loss of function for TYK2, these are very different profiles. And while some of these small molecule inhibitors are allosteric, and they can actually impact some of the scaffolding function of TYK2, they cannot actually address it fully. And so a degrader should be able to block IL-23, IL-12, type one interferon to the same level of a upstream biologics while retaining the oral once-a-day drug. Before I let Jared comment on the clinical activity, I think we're still in the preclinical, you know, investigation and characterization of TYK2 or everything that you do in the preclinical development towards IND. So once we obviously clear that, and then we'll be able to announce our phase I start.
As we've said publicly, that is, you know, roughly, let's say in the first half of the year, so roughly a year away. So we have a bit more time than what we've disclosed around STAT6. But Jared, do you want to comment on our clinical-
Yeah, I mean, I think in the clinic, I think if we have a profound effect on the IL-12, IL-23, and interferon alpha pathways, as we expect, based on our preclinical data, then I think, you know, indications including psoriasis, you know, lupus, you know, inflammatory bowel disease, the latter, what's also important there is our IL-10 sparing, which is another feature of our degrader.
Mm-hmm.
I think those are all open, you know, to us for further development, following probably an initial healthy volunteer study, that would be our first way we would start in phase I.
You have multiple interesting fronts in immunology space. Curious, do you have a plan to continuously expand the pipeline? And in terms of targeting selection strategy, what is the principles you follow?
Yeah, I mean, as I said earlier, yeah, so for sure, we're, you know, we're all in in immunology, as we said now for a while. The target selection is always, as we said, targets that have not been drugged or drugged well in pathways where there is both human validation, ideally human genetics validation on the target, and opportunity to have meaningful patient impact in terms of numbers. You know, I can say high level, we have interest in lots of areas that we believe are not well served by small molecules, and that's where we're spending quite a bit of time.
You will likely hear from us, you know, talking about a new transcription factor degrader next year that we believe is going after a totally underserved disease and population, and so we will share more once the program is closer to the clinic.
Terrific. The pivot to oncology program at ASCO, in this week, you presented a MDM2 degrader data, and what are the key take-home message?
Yeah, just as a quick reminder that, you know, KT-253, which is our degrader, this is a very potent and selective degrader of MDM2. It's given as an IV infusion once every three weeks. You know, a very important premise of this program, based on our preclinical data, is that this intermittent dosing with a degrader will be able to avoid or circumvent a lot of the typical dose-limiting toxicities that one sees with the small molecule MDM2 inhibitors, especially myelosuppression and GI tox, and therefore, have a better therapeutic index. So I think a clear objective of this study is to show that, as well as showing initial clinical activity and strong pharmacology. I think what we showed last weekend at ASCO sort of hit all those points.
I think, you know, we enrolled to date, 24 patients across five dose levels on our solid tumor lymphoma arm and across three dose levels on our leukemia arm, including mainly AML patients. I think importantly, we showed very strong pharmacology, even at lower doses, meaning clear evidence for p53 pathway activation, robust activation of the pathway that we expected from our preclinical data. Importantly, that was associated with a very favorable safety profile. What we saw predominantly was low grade fatigue and nausea. We saw very little in the way of dose-limiting toxicities. We obviously have not hit a maximum tolerated dose, and importantly, we have not seen any myelosuppression, neutropenia, or thrombocytopenia, nor have we seen any dose-limiting diarrhea. So this is all in line with this having a potentially improved therapeutic index over small molecule inhibitors.
Importantly, all this was associated with clinical activity. At the lowest dose level on arm A, we saw a partial response in a neuroendocrine tumor called Merkel cell carcinoma, and in arm B, in leukemia, we saw two major responses in leukemia. Both of these were patients with a very difficult-to-treat form of leukemia called post-myeloproliferative neoplasm AML. We saw CR in one patient at dose level two, and that patient has now gone on to hopefully curative transplant, and we also had a partial response, in a patient at dose level one, and their dose has now been escalated. So I think the fact that we've been able to see, you know, impressive initial signs of clinical activity, both in AML and in solid tumors, with this very favorable safety profile and strong pharmacology, is very encouraging to us for this program.
Great. For the full data from phase I in the second half of this year, do you think it would be informative enough to help to finalize the biomarker-based patient selection strategy for the program?
Yeah, maybe I'll take this quickly. That is our goal. Obviously, you know, we have been fortunate enough for both of these oncology programs that we haven't seen much as in dose-limiting toxicity, so our dose escalations have gone beyond our initial expectations. So, you know, again, our ability to deliver a full data set at the end of the year will require us to hit at the, the DLTs, you know, in the upcoming cohorts. So we can't guarantee that, of course, but the goal will be based on our expectation, is that by the end of the year, we should be able to provide a fuller data set. For sure, we'll give an update on our biomarker strategy.
This is a program that has, you know, huge potential, given that if we've really solved, and we believe we have, the therapeutic index. Even the potential in combo with so many agents for such a fundamental mechanism in tumor oncology will be really vast. So stay tuned, and we'll share more later in the year.
Yeah, especially given MDM2 p53 is actually the main axis, in the-
Right
cancer biology space.
Yes.
And, for STAT3, maybe very quickly, in EHA abstract, you disclosed two complete response in Hodgkin Lymphoma patients, and what's the next step for that program?
Yeah, sure. Go ahead.
Yeah, this is another, you know, very exciting program. You know, we've been able to dose escalate now through dose level six without hitting a maximum tolerated dose. We see very strong knockdown of STAT3 in both blood and in tumor, you know, with a very acceptable safety profile. And now we're seeing very interesting activity that we predicted from our preclinical models, especially in heme malignancies. You know, the premise here has always been to see monotherapy activity in heme malignancies and probably require combinations to see activity in solid tumors. In the Hodgkin's lymphoma patient, the genetics of Hodgkin's lymphoma, where there's overexpression of PD-L1, PD-L2, and JAK2, makes it very amenable, we think, to STAT3 degrader treatment.
And so seeing these complete responses in heavily pretreated Hodgkin patients now we think provides a potential avenue for developing this drug as a third-line monotherapy treatment and also developing this drug in combination with anti-PD-1 in second line or in first line. I should also just mention we've seen activity, partial responses in cutaneous T-cell lymphoma, so there are interesting opportunities there, especially, in combination.
Lastly, but very importantly, could you actually emphasize one more time what are the key milestones and the data catalysts in the next 12 months, given you have such a broad pipeline?
Yeah. So we have obviously a lot going on. So we'll have data on KT-333, again, before the end of the year. We'll have probably two early disclosures on MDM2, one on the preclinical work for our patient selection strategy and an update on a phase I. Obviously, we'll inform everybody when we dose our first subject in the STAT6 program, KT-621, which should happen also between now and the end of the year, as we said, in the second half. And then next year, even just in the first six months of next year, we'll have phase II data for both HS and AD study for KT-474, as well as phase I data for KT-621, healthy volunteer. So it'll be a busy next 12 months for sure.
Terrific. A very exciting time, and thank you for great discussion. Thanks again for coming.