Welcome back to TD Cowen's Immunology & Inflammation Summit. The next session that we have is with Kymera and their CMO, Jared Gollob. I and my team have come up with a whole list of questions to annoy Jared with over the next 20 or so minutes. We do want this to be interactive. For the investors on the line, please do submit questions that you may have so we make sure we can try to get those answered. You can either do that through the portal, and I'll add those into the list I have, or you can email me directly at marc.frahm@tdsecurities.com. With that, maybe we'll turn it over. Jared, do you want to just kind of level set people with the kind of high-level overview of status update of where Kymera is, and then we can jump into some of the specific questions?
Sure. Great. Yeah, I'll try to do that quickly. Next year is going to be Kymera's 10th anniversary. A lot has happened in the past 10 years. Our platform, our degrader platform, we think has evolved remarkably, where we can really go after high-priority, difficult-to-drug targets at will. We've moved five programs into the clinic over the past five years, showing really strong translation from preclinical to clinical. Several years ago, everybody knows we pivoted more toward immunology, and we're working on building what we think will be the industry's sort of best-in-class oral immunology pipeline. Our two flagship programs right now that are solely owned in immunology are STAT6 and IRF5. A ton has happened with STAT6 over the past year. We've completed our Healthy Volunteer study and read out those results this past June.
More recently, at plenary session meetings at EADV and ERS, we've recently announced completion of dosing in our phase I-B AD study and are going to be sharing data next month. We've also initiated our phase II-B AD dose range finding study. That was a major milestone for us in planning on initiating the phase II-B asthma study in Q1 of next year. A lot is going on with STAT6. IRF5, also a very exciting program with opportunities in lupus, IBD, and RA. We've completed IND- enabling studies for that program. We're moving it into phase I Healthy Volunteers early next year, and we'll have data readout next year for that program. From a cash runway standpoint, we're well capitalized.
We have a runway that takes us into the second half of 2028, which allows us to get through a number of key inflection points for STAT6, including the phase II-B studies. It also allows us to get through phase I and phase II in our IRF5 program and to deliver on bringing at least one to two new oral immunology programs into the clinic each year.
Great. Thanks for that. As you kind of touched on, we're in the midst of the phase I trial for 621, where you have reported the healthy volunteer data, but now you're starting to transition into patients with actual ongoing inflammation and disease. Just any biological reason that we should think of that the degradation percentage that you were able to show in the Healthy Volunteers may not translate completely linearly to these patients as you move into AD, particularly when we think about in the tissues where the action really is happening?
Look, it's an important question. I think when I was referring earlier to sort of seeing high-fidelity translation across multiple programs over the past five years, both immunology programs like IRAK4, STAT6, and Healthy's, as well as our oncology programs, I think that translation has given us a lot of confidence in expecting translation from Healthy's into patients. There isn't anything that we know about AD, or frankly, any of the sort of Th2 allergic diseases where dupi has been approved as active, where we would not expect, at least upfront, to be able to see translation from Healthy's into patients across different tissue types. Obviously, that's of great importance to us.
That was really one of the primary objectives of the phase I-B, was to be able to demonstrate translation of both safety PK as well as PD, STAT6 degradation, both blood and skin in patients compared to Healthy Volunteers. That was an important objective of the study and also important in helping us to confirm ultimately the dose selection that we'll have for the phase II-B AD study.
When you think about that kind of timeline of degradation that you were able to translate in the Healthy Volunteers and what that means for how quickly you're able to kind of turn off this pathway with a degrader, how does that compare in your mind to what is achieved when you use an antibody? There are IL-4, dupi, but also the IL-13s. Just is this a little bit faster of a mechanism to turn off the pathway, kind of similar timeline, a little bit slower?
I think the antibodies, as you know, they usually use induction regimens, which can be one dose at a higher dose compared to the others or multiple doses. I think with the induction regimens, the antibodies have shown they're able to get pretty rapid neutralization of signaling of activation of the IL-4, IL-13 pathway. I think likewise, albeit through a different mechanism with our degraders, we've shown in Healthy Volunteers that we can get maximal STAT6 degradation in blood within four to eight hours of a single dose. If you look at the kinetics of pathway inhibition, at least based on our Healthy Volunteer data, our inhibition of TARC in the blood over the two-week period of dosing in the MAD and the Healthy Volunteers look very similar to dupi's inhibition of TARC from their Healthy Volunteer study.
I think all of that gives us the expectation that we should have similar kinetics of pathway inhibition as dupi. Ultimately, what the kinetics of clinical response are going to look like with a STAT6 degrader versus what dupi has shown, I think that will have to be sort of seen over time as we look at our phase I-B data and then subsequent larger studies, phase II-B and phase III.
Okay. You started to move into TARC, which is exactly where I was going next. Just remind us kind of where you guys view the bar as to at four weeks of kind of suppressing this pathway, what that means for TARC as a PD marker and how much it should go down. Also, how robust is that number, particularly when we think about dupi's phase I, II trials being run a decade ago and assays do change over time? How do you think through that?
Yeah. I mean, yeah, great question. I think maybe we start off with what has dupi seen in order to level set. I think if you look at the dupi SOLO 1, SOLO 2, phase III data, where patients came on with very high TARC levels at baseline in the thousands, if you go and look at 28-day results within the 16-week or even one-year studies, you see about 70%-80% suppression of TARC at 28 days with dupi in those SOLO 1, SOLO 2 trials. What's interesting, if you look at dupi 's effect on TARC in other diseases like EoE and asthma, where baseline TARC levels are much lower, you see maybe 45%-40% reduction in TARC. Obviously, dupi is blocking the pathway in those patients that is highly active in asthma and EOE.
Because the starting level of TARC is lower, the percent reduction that you see with TARC is less. Same thing goes for Healthy Volunteers. Both the dupi Healthy Volunteer data, they saw mean 35% reduction in TARC. In our Healthy Volunteer study, again, where you have low normal baseline TARC levels, just as they had in Healthy's, you see about a 37% reduction. What that tells us is that the change in TARC is going to be a function of where TARC starts to begin with. I think it always has to be looked at in that context. When you have high TARC levels, we should be able to see reductions that are dupi -like for high TARC patients.
If TARC levels are lower, we should still be able to see dupi -like effects on TARC, but you have to match that up to sort of what dupi saw in patients that had lower levels at baseline.
Okay. I guess with that, is percent the right way to look at it? Percent reduction, the right way to look at it, or is it getting to kind of an absolute, getting to some sort of lower threshold?
I think percent reduction is very appropriate. I think ultimately, what we've learned from dupi is that when you're fully blocking the pathway, you can have a range of TARC reductions. You can fully block IL-4/13, which is what you're doing with dupi, and you can see, as I said, 70%-80% reductions if you're starting off with TARC levels that are in the thousands. You could see 40%-45% reductions if you're starting off with TARC levels that are much lower. I think the percent reduction, if you clearly are seeing an impact on TARC that is appropriate to whatever the starting level is, I think that is giving important information about how you're engaging in blocking the IL-4/13 pathway.
Okay. We'll get to EASI scores a bit more formally later. On your call the other day, I mean, you were kind of highlighting that maybe dupi SOLO trials were run in a world where there was no extremely effective AD drug. You got a ton of very severe disease patients who had just been suffering for years versus more modern trials of other agents are, of course, in a dupi world where the most severe patients have been treated and at least knocked down the disease some. Given that, is TARC correlated to kind of baseline EASI score, baseline disease severity, and we should expect a somewhat lower TARC baseline in any of the patients you enroll, or is it not as kind of correlated with baseline disease severity?
Yeah. I think there's an imperfect sort of correlation between TARC and EASI. If you look at some of the published data, you can see R- values of like 0.5, 0.6. So there is some correlation between EASI and TARC, but it's not an absolute perfect correlation. They don't always go hand in hand. Again, once we show our data in December, you'll have a sense for what we were seeing within our study. I think your comment earlier about EASI scores sort of drifting down over time in studies within AD is correct. The earlier dupi studies, the mean EASIs were probably in the low to mid-30s. More recent AD studies, if you look at the data that are presented out there, they're probably more in the low to mid-20s.
It's important to emphasize that even though there's been a drift down in EASI, probably, as you said, because some of the more severe patients may just be on systemic therapies and not eligible. Nonetheless, these are moderate to severe patients. If you look at dupi 's activity across the spectrum of moderate to severe, it's very active across the entire spectrum. Any study that is truly enrolling moderate to severe, whether it's on the lower end of that range or the upper end of that range, should be able to show activity. That's why we've guided that our expectation still for phase I-B, and this has been our expectation from the very time we first initiated the study, was to be able to hopefully show activity at day 28 that's in the ballpark of what dupi was able to see at day 28 in their studies.
Okay. Would that also—that potential that the baseline numbers have kind of drifted down a bit, would that also impact, not that you can show the drug is active, but the exact percent EASI reduction that you would expect should also be a bit lower, or?
No. I think one should still be able to show whether one is in that dupi ballpark. If you look across the range, actually, patients on dupi studies who are in the lower part of that range, sometimes you can actually see even greater effects on EASI compared to patients that are in the higher end of the range. In general, you're seeing robust activity, whether you're looking at EASI percent change or looking at EASI- 75, EASI- 50. I think it is important to look at the context of the baseline characteristics of the patients. You can look at the dupi data and sort of see what they were seeing when they were at the lower end of that range versus the upper end of that range.
I think in general, one should be able to sort of show within the range of patients that were enrolled onto the study, as long as they are moderate to severe patients, a dupi -like effect and be able to sort of provide the appropriate context when you're looking across studies to do those sorts of comparisons.
Of course, in later-stage trials, I think people get very focused on, including regulators, on kind of the EASI thresholds like EASI- 75. Are those thresholds, do you view them as terribly relevant in this? We're only talking 20 patients, or should we almost entirely focus on kind of the average change in EASI and kind of ignore the thresholds for now?
Yeah, I wouldn't say ignore, but I think your point's a good one, which is that when you have a small N, a small data set, continuous variables probably provide more information than the categoricals. Because as you're saying, with an EASI- 75 or 50 or vIGA 0/1, one patient or two patients either way could either make your drug look really great relative to dupi or not as good as dupi or the same. I think it is important to factor in. We're going to be showing everything. We think all the data are relevant, both the categorical EASI data as well as the vIGA data and NRS Pruritus. I mean, we're going to be showing everything next month. Yes, I think it's helpful to look at the numbers when you're looking at categorical endpoints and to put it into that context.
I think in the SOLO 1 and 2 trials at the four-week end time point, the average EASI reduction was like 50%-55%. Is that the relevant benchmark, or is there some nuance there?
Yeah. I think even though we've been, because our phase I study, because there's no placebo control, is a bit more biomarker focused, we've been more willing to sort of go out there and say, "Well, the benchmark for TARC is 70%-80%." Whereas for the clinical endpoints, just because there's no placebo control, we've been maybe a little cageier and not wanting to sort of really go out there and say, "Here's a number," and then have everybody sort of focus on that number.
I think the number you're describing is consistent with if you go to those SOLO 1, SOLO 2 graphs, whether it's for EASI or NRS Pruritus, choose your endpoint, and you draw a vertical line down to 28 days, you can look at that number and say, "Okay, this is the ballpark where if you're going to claim to be sort of dupi -like or having some dupi -like activity, that's where you'd want to be.
Maybe we'll move on from the I-B that you're about to show. You're also currently opening the II-B. Once you speak to why you've been comfortable opening that, formalizing the exact doses in there ahead of kind of the confirmation and new information that you're going to get out of the I-B.
Yeah. I think that's a fair question. I think from the beginning, we always emphasized that for us, for the program, what was most important was getting as quickly as possible from phase I-A to phase II-B. We never wanted phase I-B to be a rate-limiting step, and it has not been. I think our dose selection for phase II-B, it's fair to say, is based largely on what we learned phase I-A. we had such a large data set, over 150 subjects, safety, PK, PD across multiple doses, single and multiple doses. That provided the basis for our wanting to choose doses that would give us an adequate range within phase II-B.
I think what phase I-B provided us with is sort of that translation confirmation showing that across not just one, but actually two different doses within phase I-B, we wanted to be able to look at translation from healthiest of patients to give us even more confidence in the doses that we were selecting based on phase I-A data. We did have enough data, we felt, from the patients we enrolled on the first dose in phase I-B and then partial data from the patients who we were enrolling onto the second dose to say, "Okay, we've seen translation now," and we felt as though we had seen enough to be able to finalize the doses for phase II-B and to really get that study moving. Again, the aim was not to rush and to prematurely select doses for phase II-B. We were very careful about those doses.
We wanted to be as confident as possible in those phase II-B doses because it's a big investment, time and money for those studies, and those are critical trials for this program. We wanted to make sure that we had the right doses selected for phase II-B.
How should we think? I know you're not disclosing the exact dose levels of either the I-B or the II-B at this point, but how should we think of the relative doses in the phase II versus the phase I? Are these the three doses in phase II kind of bracketing and just broadening out on either side a little bit relative to the phase I? Is it this is kind of testing the higher end of the therapeutic range relative to the I-B lower end?
Yeah. I think with our being somewhat limited in what we can say, I think for phase I-B, we'll obviously show what those doses are when we present the data next month. What we have said is that recall phase I-A that at doses of 50 mg-200 mg, we were seeing complete degradation of blood and skin. In terms of the first dose we brought into phase I-B, it would be within that range. In terms of the second dose that we wanted to look at just for the purpose of additional translation, we haven't commented on whether it's higher or lower. For phase II-B, I think what we can say is that the doses we selected for II-B are among the doses that we did look at phase I-A, but we're not really at this point revealing what those doses are.
We probably won't until that study is completed just for competitive reasons. We are really not able to say more about the phase II-B dose selection, except to say that we obviously wanted a range of degradation. You can think about the three dose levels within phase II-B as wanting it anchored on a dose that is going to hopefully give us sort of optimal degradation and activity, then a dose that would give us maybe super maximal degradation, and then a dose that would give us maybe suboptimal or submaximal degradation. That would allow us to do what you want to do and what regulators want you to do within a phase II-B study in terms of dose range finding.
Of course, you're going to do the same dose range finding in asthma as well with a trial starting early next year. How much of dupi obviously does have a different dosing regimen in asthma and other lung diseases versus skin diseases. Do you expect to also end up with one because that's the nature of the biology of this pathway, or do you think that's more to do with the distribution of an antibody and maybe a small molecule it doesn't apply to?
Actually, for dupi , the posology, the dose and dosing interval is actually the same for those diseases. The only indication with dupi where it differs is in eosinophilic esophagitis where it's given weekly instead of every other week. Otherwise, the drug is given with the same dose and the same frequency. Now, does that mean that will be the case for our degrader? We don't know. What we have said is that we are bringing the same three doses into the phase II-B AD as we are into the phase II-B asthma. Those studies will be looking at the same three dose levels. Whether or not the recommended phase III dose that comes out of those phase II-B studies are the same or different remains to be seen.
Okay. I would say broadly speaking, a theme we see in INI is some movement towards combinations, most prominently in IBD and some of those diseases, but also some work going on in AD and some of the other Th2 diseases. Is that of interest to Kymera? If so, what targets make sense to put with, in your mind, to put with a STAT6 degrader, and when is the appropriate time to start that work?
Yeah. That's a really interesting question. Yes, I think you're right. I think combinations are definitely in the future, I think, for any company looking to build out and optimize its immunology pipeline. I think a disease like AD, even though the focus is on Th2 and on IL-4, IL-13 for good reason, it's also become clear over the years that inflammation is not always that black and white in AD and that you can have patients who also have mixed inflammation, Th1 and Th17. When you think about are there combinations that can sort of improve on the clinical outcomes in AD patients, I think the answer is hopefully yes.
From a strategic standpoint, you can imagine wanting to combine sort of a pure Th2 play drug like STAT6, maybe with drugs that are also able to pick off Th1 or Th17 and combine those sorts of agents in a disease like AD. I think those are the sorts of strategic considerations that we're already thinking about and looking into experimentally at Kymera.
Okay. Do you think you need to kind of get well down the path of phase III, if not approvals, before you would want to start that, or is that once you get the phase II-B and select your dose, you're going to start it right then?
No, no. I mean, I think we haven't really laid out that sort of a strategy with a lot of granularity. Clearly, our focus for STAT6 is on STAT6 as a monotherapy, right, in Th2 allergic diseases. Nothing is going to deflect from that focus and from our resource allocation there. I think I'm talking more about preclinically starting to look and understand what might rational combinations be. That could be part of life cycle management down the road. Certainly, our near and midterm focus is going to be on moving these drugs through phase II-B into phase III, getting drugs to patients as quickly as possible with STAT6 as a monotherapy.
Yeah. Okay. One last question just that I have been getting from investors over the last week is I think many people were taken a little bit by surprise by Pfizer disclosing that they actually have a STAT6 inhibitor that is moving into phase II-B also. Just looking through patents and other presentations that you guys have been able to find from competitive intelligence, what can you tell about that program, and how do you kind of think of it relative to your program?
I mean, we were aware that Pfizer had a STAT6 inhibitor effort. We weren't aware that they were about to embark on phase II. In terms of degrader versus inhibitor, I think we've always been very clear in our minds from our own experimental data and just what's known in general about the pharmacology of degraders versus inhibitors that it's going to be very difficult for any small molecule inhibitor, whether it's given once a day, twice a day, 3x a day, to get the round-the-clock 24/7 inhibition of that target in a way that's safe and tolerated, which is what you need if you're going to try to match the safety and activity of a biologic. We're very confident that only a degrader can really have that sort of a pharmacologic profile.
We're not concerned from a competitive standpoint in whether an inhibitor can actually match our activity. With that being said, I mean, we are obviously aware and conscious and need to be very aware of the competitive landscape and what's going on in the inhibitor space. There are also several companies that are claiming to have degraders. We haven't seen much preclinical data on those degraders, so that remains to be seen. None of these degrader drugs are in the clinic or other small molecules yet are in the clinic. It's really just the Pfizer compound that appears to now be starting phase II-B. It'll be interesting to see where that goes, but I think our bet is on degraders just based on what we know about the pharmacology and biology of degraders versus inhibitors.
Okay. With that, unfortunately, we're going to have to cut it off here. Thanks so much for joining, Jared, as well as all the investors on the line.
Thanks, Marc. I appreciate the question.