Welcome back to the 45th Annual TD Cowen Healthcare Conference. I'm Marc Frahm from the TD Cowen Biotech team. We're really pleased to have with us for the next session, Kymera, where we have Nello and Jared, Nello CEO, Jared CMO, to join us for a discussion. I've got a whole list of questions, but anybody in the audience, feel free to raise your hand if you have your own questions. We do want to get those answered as well. But maybe to start off with, Nello, you want to just kind of give a high-level overview and maybe the key takeaways from your earnings update the other day and some of the updates you provided on clinical programs there.
Thanks, Mark. Welcome to Boston. At least we have a conference in Boston. We had a call last week where we highlighted a few updates. Maybe if we go program by program. We talked about KT-621, which is our first-in-class STAT6 degrader. This is a program that we're excited about for many reasons. Maybe the unique feature of this program is that for the first time in, I would say, in the history of immunology, you can have an oral drug with potentially biologics-like activity for potentially tens of millions of patients around the world. This is a drug that has shown preclinically to have Dupilumab-like activity in vitro and in vivo systems. And in our hands, preclinically, has had a really, really compelling safety profile. What we said, a couple of things.
First is that we will share our healthy volunteer, the totality of the SAD/MAD healthy volunteer data in June. And maybe later I can explain why in June. We've also talked a bit about our phase i-B study, which actually we expect to start ahead of our phase i healthy disclosure in Q2. This is going to be a single-arm, 28-day study in atopic dermatitis patients focused on power for hopefully showing a compelling biomarker profile in blood and skin that will be able to compare to upstream biologics. In that study, we'll also measure clinical endpoint, but clearly a biomarker-focused study. So we talked about these two, again, new concepts, the phase i-B trial design, which again, we can go deeper in the next few minutes. And we've talked about the disclosure of the healthy volunteer data in June.
For TYK2, we said we're on track with filing an IND and initiating phase i in Q2 of this year. The team has done an impressive job keeping on track with the same timeline since January of last year when we first introduced this program. We also talked about KT-474 and our IRAK4 franchise with Sanofi that is on track to have data in both HS and AD in 2026. Then we're excited to finally be able to disclose our novel new program. This is going to be an early May disclosure, maybe because we wanted to obviously make sure we had a clear line of sight to IND. The program is now in IND-enabling studies, having gone through non-GLP tox. We've checked all those boxes.
And we wanted to do it in a time that would not overlap with the 61 healthy volunteer data. So we'll do that in early May. And we hope many of you will attend because it's a novel program against an undrugged transcription factor that has plenty of human genetics data tying that target to many diseases that I believe are not addressed for sure by effective and safe oral small molecules. So excited about that. So maybe this is the main update. So I'll pause here and see if we can go into any other details.
OK. Sorry to touch on some of those comments on 621. I think that's a question we fielded. Someone is trying to figure out why that data is in June. Because I think maybe there was a sense that you might be able to finish that trial a little bit faster, particularly given that you're going to start that AD trial this quarter. Can you maybe explain some of that description? What follow-up do you need before you can fully know a dose?
Yeah, I think we're today maybe in the position to add a bit more granularity into where we are with the study and why June. So we expect that we'll complete dosing of the SAD/MAD study by the end of this month, by the end of March. I want to remind everybody that when you complete dosing, we're talking about day 14. We actually follow up patients through day 38. After that, it takes us about a month to generate all the biomarker data. As you know, we go very deep with biomarker blood, skin, STAT6 degradation, other biomarkers. So it takes a month to do that after day 38. And then obviously we need to unblind the study and collate and generate all the data. So you can see if you do the math how we end up being in that month.
But again, the study has moved exceptionally quickly. And this is a testament to both our team at Kymera that has done an impressive job as well as our partner that is conducting the study. But anyway, we'll leave the celebration to later.
And so obviously if you start that AD trial a bit before June, that means you're starting it with maybe not all of that biomarker data fully analyzed. Is that accurate? And then what do you need to select a dose to go into the phase i-B versus?
Yeah, I just want to be careful with how I answer this question, which is totally pertinent. So the dose that we're planning to take into our phase i-B study is we expect a dose that hits our target product profile, which we said in the past, a dose that would be able to achieve 90% degradation, 90% reduction plus in blood and skin, and a dose that we believe has a good safety and tolerability profile. So you should expect that once that profile is reached, we would be able to initiate all the activities to initiate a phase i-B study while completing all the analysis of all the doses and unblinding all the data to report the totality of SAD/MAD might take longer.
Okay. And then as you get all that biomarker data in, you want to kind of walk through how you will evaluate dose and that you're seeing the type of PD activity you'd expect?
Yeah, I mean, I think what's really important is to appreciate how we're thinking about the development of KT-621. I think this is, for us, a potential once-in-a-generation type of opportunity with this type of program. So we want to be really thoughtful about what questions we ask in each study and what information we use from each study. So as you know, we're doing a healthy volunteer study that whose main goal is really to demonstrate degradation, safety, and obviously PK to support that. Yes, we're looking at Th2 biomarker, but really the weight of the evidence would be on degradation and safety. The phase i-B, which again, we'll read out this year too, will be heavily focused on biomarkers and heavily focused on comparing the biomarker to upstream biologics in blood and skin. We will also measure clinical endpoints.
And then the really critical path study is our phase ii-B, our phase ii-B studies, AD that will start before the end of the year and asthma that will start early next year. And so the important data that we'll actually get from the healthy volunteer study are the doses that we're going to select to initiate our phase ii-B. So you can imagine if we select multiple doses, for the sake of argument, let's say three doses, although we haven't decided yet, we want to be able to have doses that explore different levels of degradation.
So that's really where the team will spend time both generating the data and evaluating the data, because this is probably one of the most important decisions we'll ever make on this program, the doses that we will use in phase ii-B, especially given that we plan that this phase ii-B is the only phase ii study that we'll run and that out of these phase ii studies, we'll be able to select the phase iii dose that we will use for all the indications that we're going to be trying to take this drug into for registration. Just to be maybe even more clear, it is really the degradation in blood and skin that is the only assay that has the depth, the sensitivity to look at pathway biology to the level of precision that we need to make a selection.
If you've seen, for example, these blood Th2 biomarkers in healthy volunteers, they're not really able to discern those responses for Dupilumab. So if you actually looked at that, you probably wouldn't pick the dose that Dupilumab has been approved with. So that will be informative. That will be helpful. I think there will be good data to collect. But the degradation is where we're going to make a dose selection decision.
And where are those, as you get some of those Th2 biomarker data, where's the thresholds where you say the biology is kind of working like you would expect? And is there a threshold on the high end where you'd say maybe some of these hints preclinically that this mechanism might be slightly more potent than a Dupilumab?
Yeah, I want to be totally clear on this, and I know that people speculate on this comment that I make. But the impact on healthy volunteer biomarker for Dupilumab has had no correlation to the impact of Dupilumab in patients if you look at dose as well as depth. So this, I feel to me, given that it's been shown by also other mechanisms like the IL-13 from another company, I mean, you do see a change of these biomarkers. So I think this is a yes or no. But by no means I think we'll be able to compare drugs based on a 10% reduction or 5% reduction of IgE at day 14 that Dupilumab has shown or a 35 versus 30 versus 25. I don't think that's scientific. I think we want to collect the data. We'll generate the data.
We expect the data to be looking like Dupilumab because we have no reason to believe that this mechanism should have less impact on those biomarkers than Dupilumab. But I also don't want us to spend time talking about cross-trial comparison on baseline levels of healthy volunteers. It's just not scientific.
What about when we get to late in the year when we get the phase i-B data?
Yeah, that's for sure. I think there, I can say today, we haven't even generated any patients' data. So I can say even more strongly that if we don't show the depth of TARC and IgE and the periostin, eotaxin, and transcriptomic that Dupilumab has shown, then our claims I think would not be as absent that this is a Dupilumab-appealing type of mechanism.
OK. I think that that covered. Anybody want anything else on phase i before we get to OK. So now you've already kind of started to lay out that phase ii plan. Maybe it's more of a Jared question. You want to run through what you've disclosed there around trials and then we can get into some of the.
You mean the one B?
Yeah, for the well, I guess one B. Yeah, around.
Yeah, so maybe starting with the phase i-B. We've said it'll be in patients, so in moderate to severe AD patients. We'll take an optimal dose from the phase i-A study that's giving us maximal degradation. It's likely that that dose that we bring into phase i-B would also ultimately be probably the top dose in our phase ii-B. So we want to make sure that it's obviously highly active. It'll be 28 days of dosing and 14 additional days of follow-up. We anticipate enrolling approximately 20 patients with moderate to severe AD onto that phase i-B study, which we mentioned is starting in Q2. The primary objective, Nello already laid this out of that study, really the primary focus objective is impact on biomarkers. And so we're looking at multiple Th2 biomarkers in blood.
We're looking at the Th2 transcriptome in the skin, in these active skin lesions in AD. We want to be able to show a Dupi-like effect. We feel that the study, even as a single-arm study, it's a single-arm study with no placebo control, but that the study is powered to be able to show a Dupi-like impact on those blood and on those skin biomarkers. I think that's a very important part of the study. The study will also be obviously looking at STAT6. Again, in blood and skin, we expect to see a similar effect as we saw in the healthy volunteers. We will be including clinical endpoints. We actually know that if you look at the Dupi placebo-controlled studies, even at four weeks, you can see obviously a very strong effect on Th2 biomarkers in blood as well as in skin.
You can start to see some impact on clinical endpoints like EZ, for example, or pruritus NRS. We expect that in our phase i-B study, even though the primary objective is looking at those biomarker changes at four weeks and wanting to see a Dupi-like effect on those biomarkers, we will have an opportunity to look at clinical endpoints and to see if those are somewhat comparable to what has been seen with Dupi, albeit understanding that this is not a placebo-controlled study. The true test of the impact on clinical endpoints will come in phase ii-B. I think we will be able to ultimately connect the dots between impact on biomarkers, TH2 biomarkers, where you very rarely see a real impact on biomarkers in AD patients who are on placebo.
So that should be a very robust signal that we hope to be able to see in phase i-B and make the connection between that and the impact we see on clinical endpoints like EZ and pruritus and impact on STAT6.
Maybe back to some of the preclinical data. What are the kinetics of pathway inhibition of getting that degradation look like relative to when you use an antibody to hit this pathway? And should we think of, I mean, should we truly think of day 14 with an antibody as the same as day 14 with a degraded?
Yeah, I think it's very different actually, because I think if you look at, I don't know that we've actually shared the data, but we verbally have discussed that, which is we have rapid, in preclinical species, we have seen rapid degradation of the target in a matter of hours, single-digit hours. And then we can reach steady state once we reach, let's say, in preclinical species, 90% degradation, even at, again, after four hours, then we maintain that degradation for the whole study duration. Obviously, once we stop dosing, in preclinical species, the target comes back and the biology comes back. With the biologics, as you know, it does take a while, in fact, I think, Dupilumab as a loading dose concept. And so it does take a while to reach saturation. That saturation is maintained for quite a long time.
And then obviously before the next dose, you might see less saturation. So you still have a PK-dependent PD effect. For degraders, we don't have a PK-dependent PD effect. But once you give, let's say, a dose of Dupilumab because of the long half-life, you do see the biology be there for quite a while, while, again, for a degrader, it will go, it will return back to baseline soon after. We'll see in the clinic, but preclinically, a couple of days after we stop dosing. So I think the kinetics to effect for a degrader preclinically seem faster. And we'll have to see if that translates into the clinic.
As you mentioned kind of the biomarkers in that phase i-B, but with the clinical endpoints, how will you interpret the clinical endpoints given that it's not a placebo-controlled trial?
Yeah, I think it's a good question. I mean, I think we're still going to have to understand what the kinetics of response of those endpoints are to our degrader to KT-621. And I think the best way to really understand that will be in the longer studies that will be in the phase ii-B dose-ranging studies. Here we're looking at 28 days of dosing. However, yeah, as I mentioned, obviously even with Dupilumab after four weeks, you do see clear impacts on EZ. And there are benchmarks. You can look at the public literature and say, OK, this is what Dupi saw after four weeks in terms of impact on EZ. This is what they saw in terms of impact on pruritus. Whether we have to match that or not is another story.
But I think our expectation is that we should be able to see some impact. Now, to your point, in the lack of a placebo control, you have to take those data with a grain of salt. That's why our focus is really on the biomarker data, the TH2 biomarker data, and STAT6 for the initial proof of concept. But I think when you look in the totality of the data, if the clinical endpoints like EZ and pruritus are tracking together with the impact on biomarkers, which the study is powered to show an impact on STAT6 in blood and skin, I think that'll be a very compelling package to give us even more confidence in what we expected and see in phase ii-B when we will have a placebo-controlled study. And obviously, we'll have a longer study.
It's a longer study where you can really, it's more relevant to then look at placebo as a control. For example, the typical AD studies are 16 weeks, and that's a better vehicle for really understanding activity versus placebo in benchmarking it.
How much will this phase i-B really inform your phase ii-B trials? Because if you're starting, if this isn't going to read out until almost year end and you're starting a phase ii-B for year end, is there really much opportunity for this to even inform it? Is that all driven by healthy volunteers?
Yeah, I mean, I think our plans for phase ii-B is driven off the healthy volunteers. But the phase i-B data are an important validation of our strategy. We selected those based on the degradation profile in healthy volunteers. We want to demonstrate that the degradation profile is maintained. We also want to show that our expectation in terms of impact on biomarkers and, to be honest, also on clinical endpoints is in line with expectation because we also want to generate data to support the study enrollment. I think showing that this is a drug that actually has an impact on Th2 inflammation in patients. We'll have, I don't want to go into the details of all the biomarkers at some point we'll share, but we have a plethora of things that we're going to look at.
Some are quite creative that I think will be highly, highly informative and supportive of the existing strategy, and importantly, I think for PIs and for patients that will hopefully also see the data and be excited by it, because this will be the first Th2 oral drug that is going to be evaluated in the clinical setting from this pathway. So I think everybody that we've talked to is comfortable with the biology of saying, we understand how this biology works, and so I think we have, we feel like we have the attention of investigators and KOLs, and obviously, these are the sites that are going to help us also enroll, but obviously, showing data increases their reason to believe, so it's an important study.
Maybe Jared, do you want to describe the phase ii-B's that have been disclosed?
Sure, to the extent that I can, because I think there's limited information we've put out there, but in broad brush strokes, I think Nello alluded to this earlier. Our aim is really to have two phase ii-B studies. We would call them sentinel phase ii-B studies that will then determine dose for registrational phase 3 studies across multiple different indications, so the sentinel phase ii-B's, one is going to be in moderate to severe AD that will kick off in Q4 of this year. That's what we've guided, and the other one will be in moderate to severe asthma that will kick off in Q1 of next year, so we envision that those two phase ii-B's, both the placebo-controlled dose range finding studies, will allow us to select the dose for phase iii registrational studies across multiple indications.
For example, that AD study will inform dose for other derm indications and probably even for GI indications like EoE, whereas the asthma phase ii-B will inform dose for COPD, for example, or chronic rhinosinusitis or other sort of respiratory indications. That we see as a very efficient way to get to the doses that we need for phase 3 and then enable multiple potentially multiple parallel phase 3s across multiple different indications where in the past, Dupi has been either approved or shown to be effective. I think that's really the most we can say in terms of dose-ranging studies, placebo-controlled. Again, in very broad brush strokes, if you look at phase ii-B studies in general, they tend to be 200-250 patient studies.
But we haven't determined that exactly yet or the number of doses that we're going to bring into it yet. And the duration will depend on the endpoints. A typical AD study, for example, will be a 16-week dosing duration.
Dupi does have a handful of different dosing paradigms across diseases, but both kind of chronic dose. Sometimes there's also loading dose. How much of that type of stuff do you think you need to explore? Or is an oral molecule, the distribution is much more standard and you can just have likely end up with one dose across everybody?
Yeah, so I think there's kind of two questions in there. One is, do we foresee different dosing paradigm, meaning more frequently than once a day or less frequently than once a day? The answer is no. This is going to be a once-a-day oral drug. And we believe that thanks to this mechanism, we should be able, based on the preclinical data, to suppress this target to levels that we've seen to be therapeutically relevant, again, preclinically. So then the question is, will we see different pharmacology in different disease types? Let's say in derm, which I'm sure will have a skin exposure and degradation component. We don't know. Personally, I don't know how big is that component. But let's assume there is a skin degradation and exposure component.
And then, let's say in asthma, there will be, let's say, in respiratory indication, there is a systemic and a, let's say, a lung component of exposure and degradation. So it is possible that you might end up having two doses because the distribution profile of the drug in lungs and in skin is different. Based on our preclinical studies, we don't have any indications that that will happen. So to be honest, we expect that likely this will be a dose for everything. But that's the beauty of drug development. We will run the phase ii-B studies with that goal in mind, right? Evaluate which dose, which means which PK, which exposure and degradation profile is benefiting AD patients versus which dose is benefiting asthma patients. And then we'll hopefully then select the phase iii. Unlike biologics, we don't need a loading dose.
We don't need a frequency change, and so it's much simpler in a way. In a way, it's a much simpler development path.
OK. And just, you've got a handful of different trials here starting up this year between them. What's the kind of disclosure strategy? Or do you plan on informing the investment community when you start dosing in the phase, have actually started dosing the phase i- B? Or is no news good news?
Yeah, no, I think as we've done often, or almost always, we like to say when the study starts. So it's likely that it's not going to have to be the day off. But once we start the dosing of phase i-B, we'll share that. Obviously, once we are closer to data readout, we'll obviously communicate when the general expectation of data release will be. When we start our phase ii-Bs, I'm sure we will share when those will start. So yeah, I think this is an important program, and these are important milestones in a way. So yes, we'll share them.
Maybe turning to another program that's about to enter the clinic, the TYK2. I think many in the investment community have kind of soured on that as a target. What do you think they're missing?
They're missing the power of targeted protein degradation. I mean, I totally appreciate the sentiment. There has been lots of undifferentiated TYK2 inhibitors. I'm not saying they're bad molecules. They're just highly undifferentiated, and so if you say, we're going to have another TYK2 agent, the first answer is, why? Right? Some would say, but I think we're talking about a totally different pharmacology. I think for the first time, we are pursuing a TYK2 loss of function phenotype, which is definitely not what small molecule inhibitors can do. They can't even inhibit the pathway fully 24/7, so I think we have to give ourselves, or you should give us the benefit of the doubt that this is totally different pharmacology, and we've shown this for IRAK4 already.
And in this case, with a clinically proven target, I think the opportunity of having a clinically differentiated asset is higher even than what we've done before with IRAK4. So I think it's learning about human genetics. We have a slide on our deck that shows the human genetic loss of function versus the kinases- dead profile. And obviously, they're very different. And the allosteric inhibitors are not, they're not replicating necessarily only the kinases- dead, but they're not also blocking all the scaffolding functions of TYK2. So we believe that this is going to be a program that will surprise all the skeptics, which seem to be 99% of people these days. But that's OK.
Maybe over 100%.
That's possible, well, if you take.
You want to lay out kind of the early plan, the phase i and how quickly we might know that that's really what Nello just described is playing out and starting to drive different clinical outcomes that we've seen.
Yeah, yeah. So the phase i study will start in Q2, which will have a readout in Q4. I think really, as a healthy volunteer SAD-MAD study, that phase i trial is going to be key in showing that loss of function phenotype biology by looking at the pharmacodynamics. So we think that within that SAD-MAD study, by looking closely at TYK2 levels in blood and skin, we're going to be able to hopefully show that differentiated pharmacology that we can degrade TYK2 by more than 95% round the clock, so 24/7, to allow us to have that full round-the-clock pathway blockade that would mimic TYK2 loss of function. And we'll also have other pharmacodynamic assays that will help to show that we're fully blocking IL-12, IL-23 type 1 interferon pathways while sparing IL-10. Again, that's by removing both scaffolding and kinases activity.
That's something that we think is going to be unique to a degrader relative to what the small molecule inhibitors can show. I think if we demonstrate that in phase i, that will be key in showing that differentiated pharmacology. And then the next step for us next year, and we've provided some color around this, would be to have a placebo-controlled sort of proof of concept study in an indication where TYK2 inhibitors have been active, for example, in psoriasis. And that would be a vehicle to then be able to show importantly that a TYK2 degrader has biologics-like activity in a disease like psoriasis, comparing it to placebo, which would differentiate it obviously from the small molecule inhibitors that have all come up short of biologics-like activity.
That would be the package that would compel us to want to move forward then with further late-stage development.
I mean, biologics in psoriasis have their own range.
Exactly.
Do you just need to be in that range? Or do you need to be at the top?
In that range. In that range would be a huge win.
OK. Unfortunately, that's all the time we have. So we're going to have to cut it off there. But thanks very much, Nello and Jared, for joining and everyone in the room.
Thanks, Mark.
Thank you.