Hi, everyone. Welcome back to TD Cowen's Oncology Summit here ahead of ASCO and EHA, which obviously also has an oncology component as well. We're really happy to have with us for the next session here, Jared Gollob, the CMO of Kymera Therapeutics, who, of course, has programs in oncology, but also a lot of else going on. Although we will keep most of the conversation here to these oncology updates that are coming over the next few weeks, both in the form of the abstracts we've already seen and the presentations coming at ASCO and EHA for their programs.
I have a question list that my associates and I have come up with that we'll run through, but we also would love this to be interactive, so please feel free to submit your own questions, and you can email those directly to me as well at marc.frahm@tdcowen.com, and then I will pepper those in as well for Jared. Maybe just to start off with, Jared, do you wanna kind of level set everybody, provide kind of maybe a high-level update on kind of where Kymera is and kind of what you view as the main milestones over the next year or so, broadly, but also particularly within oncology?
Sure. Yep, thanks for having me, Marc. Yeah, happy to summarize our pipeline and the main milestones for this year and next year. You know, we currently have three programs in the clinic. You know, the two oncology programs, MDM2 and STAT3, that you and I will be talking about shortly. We also have the IRAK4 program through Sanofi, which is now in Phase II in hidradenitis suppurativa and in atopic dermatitis. And, you know, we expect to have our STAT6 program in the clinic in the second half of this year, and our TYK2 program in the clinic next year.
In terms of milestones, you know, we're providing updates on the two oncology programs at ASCO and EHA in June, and then expect to provide additional information, more final data, after completing dose escalation, and providing more direction on where we're going after Phase 1A, later this year, hopefully at a medical meeting. With regard to the IRAK4 program, the intention is to have a readout for both of those
Phase II studies in next year, in 2025, in the first half of next year. As I mentioned, we expect to have the STAT6 program in the clinic in the second half of this year, with data readouts next year, and then TYK2, Phase 1 in the clinic next year, with data readouts also in 2025. So a lot going on, this year and next year in the clinic for us, both for oncology as well as for immunology.
Great. Thanks a lot for that, Jared. Maybe we'll dive in first with the MDM2, so KT-253. Can you walk through kind of the approach here with a degrader? Kind of what's similar to what's been done with other things trying to target MDM2 and the p53 pathway, and really, you know, how does this differ because of the degrader, the degrader aspect?
Yeah, I think the degrader angle is the important differentiator. You know, as you know, there have been a number of MDM2 small molecule inhibitors in the clinic over the past five plus years, and, you know, mechanistically, the inhibitors are blocking the MDM2 p53 interaction, which leads to p53 upregulation and p53 pathway activation. But what happens when you do that is you also get this feedback loop, in which when p53 goes up, there's a loop that then further upregulates MDM2, which then battles with the inhibitors to try to further activate that pathway.
And that's been one of the main limitations with the MDM2 inhibitors, not being able to sort of stimulate the p53 pathway as strongly as one would like, having to keep constant pressure up on that pathway, which then leads to the expected dose-limiting toxicities of myelosuppression and GI tox, which has limited the ability to push dose and to dose chronically. And I think, you know, this has been one of the major limitations of the inhibitors. The degrader gets around that by degrading the target.
So when we degrade MDM2, we get strong p53 pathway upregulation and activation, but we then are able to avoid this feedback loop, so we don't get upregulation of MDM2. So we get a much stronger proapoptotic effect through the p53 pathway activation, and we can also use short, intermittent dosing.
So for example, we have a once every three-week regimen that we use in the clinic now, and this intermittent regimen was derived from our experience preclinically in vivo models, showing very strong anti-tumor activity in p53 wild-type sensitive tumors when you come in with just a once every three-week dose of the drug.
So we think that intermittent dosing of a degrader can give us a stronger effect on the pathway, better safety, and therefore a better therapeutic index, and that, we think, can result in real progress in the clinic in both liquid and solid tumors that are p53 wild type compared to what's been achieved so far with the inhibitors.
Maybe just to dig on that a little further, I, I guess, the idea here, it's the, is it the degradation itself, or is it that's different, or is it the fact that your molecule kind of has this catalytic ability to degrade versus a, a one-to-one nature of a, of an inhibitor?
Well, the degrader, I mean, very effectively, you know, gets rid of MDM2. You know, we can, we can deplete MDM2 by 90%-95%, and when you deplete MDM2, you know, to that extent, you're able to get a much stronger trigger of the p53 pathway activation than you can with an MDM2 small molecule inhibitor. And when you get a much stronger induction of the pathway and of apoptosis, you also don't need to have chronic exposure to the drug.
You can essentially lower the target, you know, for, you know, 12-24 hours and get this maximal, proapoptotic effect. It's sort of like a hit-and-run approach, and then be able to have the drug essentially get cleared and the pathway to recover, but you've already committed cells to apoptosis. And so by using the degrader approach, not only do we get a very strong effect on the pathway, even stronger than with the inhibitor, but we can have an intermittent effect, you know, just a transient effect that then commits cells to apoptosis.
The transient effect is what allows you to avoid the dose-limiting toxicities of myelosuppression and GI tox because you have this positive feedback loop with MDM2 being upregulated in response to the inhibitors. The inhibitor is constantly fighting against that upregulation, and so you can't come in with the same sort of brief intermittent dosing that you can with a degrader and get the same effect on the pathway and the same favorable therapeutic index, you know, which we're able to achieve with our degrader at, you know, KT-253.
Okay. Helpful. And then you started to touch on this a little bit, but based on kind of preclinical, what is that kind of optimal degradation profile you're trying to solve for in the clinic, both in terms of that initial depth, but then, you know, what type of duration do you really want, exposure at that depth of the degradation?
Yeah, I think what we've learned preclinically in both our in vitro models and in vivo is that getting 90+% degradation of MDM2, you know, for the initial, you know, four to eight to 12 hours, is really what's needed to induce a very strong pro-apoptotic response. And we've shown that in p53 wild-type, you know, cell lines, you know, both, you know, liquid and hematologic diseases as well as in vivo.
And we've shown that in vivo, you know, dosing just once every three weeks, so an infusion given once every three weeks, you know, to animals, to rodents in these xenograft models, lead to very strong anti-tumor activity. Essentially, you know, regressions in sensitive p53 wild-type solid tumors as well as liquid tumors.
So, the profile we're looking for is intermittent, you know, deep suppression of MDM2, leading to this very strong upregulation of p53 and p53 pathway activation, which commits cells to apoptosis and then allows one to then see tumor regressions, you know, over the ensuing, you know, weeks that follow that single dose. That's the sort of PK/PD pattern that we wanna be able to see, the sort of intermittent hit-and-run approach that, again, allows us to dose intermittently like this and avoid the toxicities that you see with MDM2 small molecule inhibitors.
Okay. And so the Phase I's been running. You can walk through just kind of the design there of, you know, the dose escalation, kind of where, where you are working towards that profile that you, that you just laid out, but also kind of what, what tumor types are being enrolled with, you know, the amount of p53 kind of the wild type. You know, it's not really mutated, it's the wild types, but, you know, that we should be expecting kind of in this trial as a result.
Yeah, so the study design, so it's a Phase 1A dose-escalation. There are two arms. Arm A is for solid tumors and lymphomas, and Arm B is for high-grade myeloid malignancies, as well as ALL. So we're dose-escalating actively now across both arms. When we initially presented data last November, you know, we reported the results on the first several dose levels in Arm A. And at that time, we, we reported that we had a major response, a partial response in Merkel cell carcinoma, which was very encouraging to us because we had preclinical in vivo data showing sensitivity of that tumor type to our degrader.
Since then, you know, we've enrolled, you know, additional cohorts now on the solid tumor lymphoma arm, so we, we've enrolled, as of this abstract, you know, four dose levels, and we've also enrolled several dose levels now on Arm B, the high-grade myeloid malignancies, which includes AML. You know, what's very interesting now is we're also now seeing major responses in leukemia. So here we have 2 AML patients. You know, both of these patients have what's called post-myeloproliferative neoplasm AML.
These are very refractory, difficult-to-treat leukemias, and we've had major responses now in both of our initial two patients with that particular subtype of AML. One has been a complete response who will eventually be going on to transplant, and the other is a partial response.
Most importantly is that in addition to seeing these important major responses, both in solid tumors and in AML now, we've also seen very strong evidence for pathway engagement. So for us, the surrogate markers of MDM2 degradation are upregulation of p53 pathway biomarkers, including GDF-15, the cell cycle inhibitor, CDKN1A, and the proapoptotic protein, PHLDA3. We're actually looking at the transcripts, the RNA transcripts in the blood for CDKN1A and PHLDA3, and we're looking at plasma levels of GDF-15.
And we're seeing strong upregulation of all of these markers across actually all of the dose levels, even at the lowest doses. You know, we're starting to see a dose response, but even in dose level 1, we're already seeing upregulation of these biomarkers of p53 pathway activation, which is why we're seeing responses in AML and even in solid tumors, you know, at the earliest, at the lowest dose levels.
What's also very important has been the safety profile that we've seen in conjunction with this pharmacologic activity and with the clinical activity, in that we are not seeing any significant myelosuppression or any significant GI tox, like dose-limiting diarrhea. We have had some relatively low-grade nausea and fatigue in some of our patients, but these have rarely been dose limiting, and we have continued to dose escalate.
Again, importantly, we haven't seen the sort of toxicity that normally hinders the ability to dose escalate for the small molecule inhibitors, which is neutropenia, thrombocytopenia, and intractable diarrhea. All of that is in line with our seeing a very favorable therapeutic index so far for the drug.
Okay. Maybe we'll come back to the safety in a minute, but just on that biomarker piece, I guess, you know, you talk about starting to see these changes in the pathway downstream of p53 or associated with p53. I guess, based on your preclinical knowledge, but maybe also what's been shown with some of these older inhibitors, just what are, is there a threshold effect that you need to get over with these biomarkers to really drive that apoptosis? Is it just more is always better? Just, you know, how should we think about those biomarkers?
Yeah, it, it's a good question. There doesn't appear to be a threshold, effect per se. I mean, I think clinical trials with small molecule inhibitors have shown sort of a dose responsiveness to these biomarkers, especially to GDF-15, which has been looked at with the small molecule inhibitors. We're actually now adding these other two, transcript biomarkers, CDKN1A and PHLDA3, which have been looked at less commonly. Our expectation is that there, there aren't threshold levels, but you can clearly see, you know, strong upregulation in the expected kinetics, where you see upregulation.
With our drug, after a single dose, you see it peaking within the first 24 hours, and then you start to see recovery, over the next six or seven days. That's very consistent with the sort of effect that we wanna see, where we wanna see robust upregulation, but for a relatively limited period of time, followed by recovery. We think that's gonna be important for us to be able to achieve efficacy, but also to be able to achieve the sort of safety profile that we want.
Right. You mentioned the responses you're starting to see. Maybe can you talk about the p53 status and how to think about that? And maybe also, you know, your selection strategy kind of moving forward, 'cause I think it's broader than just p53 status.
Yeah, you know, we don't have a requirement on the study for patients to be p53 wild type, but we are typing every patient retrospectively. In the future, we likely will restrict to p53 wild type. With that being said, you know, we have, you know, sequenced a number of the patients who have come onto the study, and those who have responded, the ones that I've mentioned so far, that we've been reported in the abstract, have been p53 wild type. But I think as you're getting to markets, it's really necessary but not sufficient, you know, the p53 status.
It'll be important for these patients to be wild type for p53, but it goes beyond that in terms of trying to determine which types of patients are gonna be sensitive to treatment. You know, it's been very encouraging that we've seen sensitivity in tumor types, where preclinically, we've seen strong anti-tumor activity in vivo, and that includes a neuroendocrine tumor-like Merkel cell cancer, as well as these two AML responses, where preclinically, we've seen very strong activity also with our drug, both as a monotherapy and in combination.
I think we have ongoing work really examining all of our preclinical models and even starting to incorporate some of our clinical data to see if it's possible to come up with a gene expression signature of sensitivity, potentially, for solid tumors and/or for liquid tumors that might allow us in the future to select specifically for patients who are more likely to respond to our drug.
I think looking at things like, you know, MDM2 amplification, for example, has not really been very successful in the clinic to date with regard to the MDM2 inhibitors. And so that's why we've embarked on a more sort of comprehensive analysis of response and factors involved with response, including gene expression factors. And our hope is that later in the year, we'll be able to present an update on what we've learned and how we might be able to use that moving forward to better enrich for patients most likely to respond to our drug.
Okay. And in terms of dose escalation and kind of schedule finding, should we view maybe this and the, you know, the more details we're gonna get at ASCO as, look, you, you've got your likely dose and schedule. It's now between here and the end of the year, it's getting enough patients to figure out, you know, what that safety efficacy looks like at that dose? Or is there still more going on from a kind of dose exploration perspective?
Well, I think as of the abstract, you know, we were still dose escalating. And so I think our expectation is that, you know, this, you know, ASCO presentation will be an update of where we are. I think our expectation is that later in the year, and preferably at a second medical meeting, we will have completed, hopefully, dose escalation by that time across both arms, and we'll be able to present those data and then provide more guidance in terms of, you know, what tumor types have been sensitive so far, and where we think we're going beyond Phase 1A, you know, both for liquid and solid tumors.
Okay. And you also brought up the safety side, right, where of course, you haven't seen much at all on the kind of traditional toxicities of this class around, you know, kind of hem counts. But you have seen some kind of nausea, fatigue, headache. I mean, can you maybe just dive into that a little bit, kind of talk through the severities you're seeing, but maybe also the timing? Like, is it really just kind of Cmax-driven? Is it seen throughout the dosing cycle? Just all those types of issues.
Yeah, I mean, we noted, you know, toxicity such as nausea and fatigue as being in more than 20% of patients. But again, we actually have still seen it, you know, in a minority of patients overall. You know, the nausea and fatigue have really been largely Grade 1, Grade 2. There was one patient where they had both Grade 2 nausea and fatigue, and even though both were Grade 2, the patient decided that they wanted to stop therapy, so they were discontinued based on patient choice, but it wasn't because of Grade 3 toxicity.
The nausea in general that we've been seeing, you know, happens, you know, within a day or so after the infusion. You know, it tends to last several days. Sometimes it is treated with antiemetics, which is sort of common practice and responds readily, and then patients are fine and able to go on and get their next dose. So I think what's been important is that it has been, first of all, sort of seen in the minority of patients overall, has been largely Grade 1, Grade 2.
There have been a few occasions where we've used antiemetics effectively, and importantly, it hasn't really been for the majority of patients dose limiting, except for that one patient who had the Grade 2 fatigue and nausea.
And maybe as you can finish up the dose escalation through the year, you know, since the biomarkers don't necessarily have a threshold effect, is it really about just continuing to dose until you eventually find an MTD or you know, stop getting greater exposures, or is there some other metric as to that'll drive kind of when you stop dose escalating?
Yeah, I think that's a really important question. The short answer is, it, it could be any of the above. You know, it's possible that, that we might push and start to see those limiting toxicities, and then we would push until we reach a maximum tolerated dose. It's also possible that if we don't see or if we continue not to see dose-limiting myelosuppression or GI tox, then, you know, ultimately, how far we go in terms of dose escalation might be more a function of what we're seeing with regard to these, biomarkers of p53 pathway activation and what we see with regard to clinical responses.
Okay. With that, maybe one last question before we move to STAT3 quick for a few minutes is, just in terms of right now, it's all monotherapy, but of course, some of the longer-term plan here is potentially combinations in places like AML, where, you know, things like azacitidine can be important. But otherwise, what are the priority kind of combinations in your, in your view, and, and what do you really need to establish to start opening those? You know, given that now you've got reasonable degradation happening, reasonable safety already in place from a monotherapy.
Yeah, you know, I, I think the combinations could be very interesting, both in solid tumors as well as in leukemia. I think, you know, we've done the most work preclinically, looking at combinations in AML. You know, we've seen very strong, you know, synergy when we combine drugs like venetoclax, for example, with KT-253 in different, in vivo or PDX AML models, you know, including models that are, resistant, you know, to, venetoclax.
And so that probably is one of the highest priority combinations is for some sort of a venetoclax combination together with KT-253 and exploring that in AML. I think there could also be some interesting, you know, combinations in, in, in solid tumors, which we haven't yet explored as extensively preclinically.
But in answer to your question, in terms of what we need to see with monotherapy first, I think it'll be important for us to understand how far we can go with pressing the dose, you know, what the real safety profile of this drug is as a monotherapy, as well as the clinical activity we're seeing in AML and solid tumors with the drug as a monotherapy and the effect on these biomarkers.
Once we have a good handle on that, then I think that would be the appropriate point to start to look at the combinations and start to do sort of limited dose escalation with combinations of interest, probably starting with AML. And that's something that I could see us potentially, you know, starting and doing, you know, sometime next year, once we've completed monotherapy dose escalation later this year.
Maybe in the few minutes we have left, we'll move to STAT3. You wanna kind of give that high-level update of kind of where that program is at, particularly in light of the EHA abstract?
Yeah, I think we're also very excited about the progress that we've made, you know, in our STAT3 program. You know, I think, you know, at the end of last year, you know, we presented an update, you know, at ASH. You know, we're now building on that update. And I think what's very important, along with the fact that we've been able to continue to dose escalate, without seeing dose-limiting toxicities, even though we're getting very strong, degradation of STAT3 in the blood, as well as in the tumor.
What's very important are some of the clinical responses that we've been seeing, especially in liquid tumors. At the last update at ASH, you know, we reported one partial response in classic Hodgkin's lymphoma. We now have two complete responses in classic Hodgkin's lymphoma, which we're very impressed by, given the fact that these were both in patients who have progressed after prior checkpoint inhibitor and prior Adcetris therapy.
So, you know, very interesting to us to see that level of activity in Hodgkin's lymphoma with both of these patients, you know, potentially being able to go on to now get curative stem cell transplants. It's very interesting from the standpoint of Hodgkin's lymphoma, just because genetically the majority of these patients have a copy gain at chromosome nine in both JAK2 and in PD-L1 and PD-L2.
And mechanistically, this provides a strong basis for why these patients respond to anti-PD-1 drugs, but also might provide a strong basis for why they're responding to our STAT-3 degrader, since most of these Hodgkin's patients also have strong phospho-STAT3 expression in the nucleus of the malignant Reed-Sternberg cells. So very interesting to see that activity in Hodgkin's lymphoma.
Also, in cutaneous T-cell lymphoma, you know, we've reported three partial responses in heavily pretreated CTCL patients, which is also in line with our preclinical data, where in a STAT-3 transgenic model of CTCL, we saw very strong antitumor activity with KT-333. So these clinical responses in both CTCL and Hodgkin's, I think, are very interesting to us in providing additional direction for where we can go with this drug as a monotherapy.
We've also reported stable disease prolonged stable disease in four solid tumor patients. So those are the data that are in the abstract, and we'll be able to provide, you know, a further update on those patients, in the poster presentation at EHA next month.
Okay. And are those where you're seeing some of the single-agent activity happen, and there were these hypotheses going into the clinic? Does Kymera view those opportunities as large enough on their own that they're commercially viable to kind of move forward, or do you really need to be convinced about this solid tumor combination opportunity to justify any advancement of the program?
Well, but I think we do. You know, I think we have stated previously that we do have a high bar, you know, for moving programs, you know, in any of our programs, including oncology forward, you know, based on, you know, phase 1a data that shows us that we have, you know, a drug that could be potentially transformative. The solid tumor opportunity certainly is important for STAT3, you know, and again, we've seen predominantly stable disease in the clinic in a minority of patients.
We do have preclinical data showing strong activity when combined with anti-PD-1, and so we have been interested in that opportunity. It's not something that we're gonna pursue right now in phase 1a, but that could be a potential combination opportunity that we could either do on our own or in conjunction with a partner, you know, with the latter being more likely.
With regard to monotherapy activity, I think if we have activity which could be transformative and, and clinically meaningful to patients where there's high unmet need, and the activity that we're seeing in Hodgkin's, for example, where we're seeing, you know, a multiple complete responses in heavily pre-treated patients, that is something that we could consider, you know, further developing on our own, as a monotherapy, you know, beyond Phase 1a, or could also consider developing in conjunction with a partner.
So I think there's a very interesting monotherapy, you know, play in Hodgkin's lymphoma, as well as a combination play, for example, combining with anti-PD-1, which is also a very active drug in Hodgkin's lymphoma. So I think these are things that I think are on the table.
I think our intention is to continue to further enrich for these classic Hodgkin's patients, as the study proceeds, through the rest of this year, to get more experience in Hodgkin's, and to see whether or not we do have a high overall response rate and a high complete response rate in that disease, which could make, you know, a compelling case for wanting to move that drug forward beyond phase 1a, again, either on our own or in conjunction with a partner.
And again, I think there we'd be potentially looking at development opportunities either in third line or beyond as a single agent or in second or even first line in combination with, for example, anti-PD-1 drugs.
I think those alterations that direct, you know, in, well, PD-L1, regulation that happen in Hodgkin's lymphoma are, are observed elsewhere, may not nearly as commonly, but they are observed in solid, in some solid tumors, some other liquid tumors. Is that a path forward, even as a monotherapy, maybe?
Well, well, it's really interesting because, you know, STAT3 actually does play a role in PD-L1 and PD-L2 expression. And so, you know, it makes sense that in a disease like Hodgkin's, where PD-L1 and PD-L2 are upregulated, and that upregulation might be in part from JAK2 upregulation and activation, as well as from this PD-L1, PD-L2 amplicon, that, you know, STAT3 degrader might be acting in two different ways in Hodgkin's.
It might be impacting JAK-STAT signaling and having an anti-proliferative or pro-apoptotic effect, but it may well also be downregulating PD-L1 and PD-L2, and giving one an actually, an anti-PD-1-like therapeutic effect.
That also leads back to our interest in the degrader in solid tumors, where our preclinical data, we have seen synergy in combination with anti-PD-1, and that synergy might trace back to a similar mechanistic basis where, you know, degrading STAT3 may be having an effect on PD-L1 and PD-L2 expression, which could result in, in part, for this combinatorial effect that we're seeing together with anti-PD-1 in solid tumors.
So I think it's very interesting to us that there could be a monotherapy path as well as an anti-PD-1 path, which mechanistically makes a lot of sense in Hodgkin's, and that same anti-PD-1 combination path, you know, could also make sense in certain solid tumor types that are responsive to anti-PD-1 drugs.
Unfortunately, we're running over, so we're gonna have to cut it here. But, thanks a lot for joining, Jared, and for everyone else on the line.
Yeah, thanks for having me, Marc.