Kymera Therapeutics, Inc. (KYMR) Earnings Call Transcript & Summary

All right. Well, thank you, everyone, for joining us in our fireside chat with Kymera Therapeutics. Yes, I'm told that if you have questions, you want to ask in the audience, please scan the QR code and then you're able to ask a question, and then I will be able to pick it up here on the iPad and ask you questions. So please feel free to scan the QR code and then put your questions in there. All right. With that out of the way, it's our great pleasure to welcome Jared Gollob, Chief Medical Officer of Kymera. Jared, thank you for joining us.

Yes. Thanks, David. Thanks for having me.

That's great.

Well, for those probably new to the Kymera story, can you just give a quick overview of the company, your degrader platform and then any key assets that investors should pay attention to?

Sure, happy to. Yes. Next year, we'll be celebrating -- Kymera will be celebrating our 10th anniversary since we were founded by Nello Mainolfi and Bruce Booth. We were founded with protein degradation really as our platform, and really with the aim being to turn protein degradation into transformative drugs for diseases with high unmet need. There's been a real evolution over the past 10 years. Our platform itself has evolved considerably to the point now where we can really address very difficult-to-drug targets, transcription factors, multifunctional proteins almost at will based on our chemistry technologies. We've moved 5 programs into the clinic over the past 5 years, showing very nice translation from preclinical to clinical. And we're -- we've learned to really marry our technology to the sorts of targets and pathways where we think we can be most impactful several years ago, really pivoting more toward an immunology focus. And we feel like at this point, we have -- we're on route to having the, hopefully, best in industry sort of oral immunology platform. Right now, our solely owned program is of greatest interest to us and others include our STAT6 program in immunology as well as our IRF5 program. And we've really made a lot of progress on those programs with STAT6. Just over this past year, we've moved it through a Phase Ia healthy volunteer study, presented data last June. We've moved it through Phase Ib and are presenting data in December on that. We've initiated our first Phase IIb study in atopic dermatitis and plan on starting an asthma study, Phase IIb early next year. So a lot going on with that program. And for IRF5, our KT-579 program, very excited about that as well, planning on moving that into Phase I healthy volunteer study next year. And then lastly, we're fortunate to be well capitalized. We have a cash runway that takes us into the second half of 2028, which is -- which will enable us to get through key readouts for both of our Phase IIb 621 studies in AD and asthma, also key readouts for the 579 program and our plan to bring at least one additional immunology program into the pipeline each year.

Excellent. That's a great overview. Thank you so much. So let's start with the lead program, KT-621, which is the STAT6 degrader. Maybe just start things off, can you review why a STAT6 degrader should be more effective than inhibitor?

That's a really important question. STAT6 has been in everybody's sort of target over the last 10 years because it really controls signaling through the IL-4, IL-13 receptors. Those pathways having been well validated by drugs like DUPIXENT. So there's been a real desire to try to develop an oral drug that can block STAT6 and phenocopy what DUPIXENT can do. You can imagine how transformational that can be for the field where DUPIXENT right now only really penetrates a very small percentage of all the moderate-to-severe patients with, say, asthma and AD, an oral drug could really open up that segment. The reason for degrader is, degraders have a catalytic mechanism. Degraders are heterobifunctional small molecules that co-opt an E3 ligase, and binds ab E3 ligase into a protein of interest, brings them into proximity, leads to ubiquitination and degradation. It's catalytic because one molecule of a degrader can degrade thousands of copies of its protein. So there's a connect between PK and PD. So even when the drug is cleared, tiny amounts of drug in the cell are still mediating profound deep degradation, which is the reason why you can dose once daily with a degrader like KT-621, STAT6, and fully suppress that protein round the clock, 24/7. And that's the only way you can match both the efficacy and safety of antibody biologic. Small molecule inhibitors really are very exposure based, right? So as the exposure waxes and wanes after a dose, so does the activity against the target. So it's very difficult, if not impossible, to get 24/7 full suppression of a target like STAT6 usually using an inhibitor. So we feel that the only way to match the activity of a biologic by targeting STAT6 is to use a degrader.

Got it. And then just on that front, I mean, you recently just provided some healthy volunteer data. Could you maybe just provide a quick overview of the data? And what were the most important key takeaways from the initial clinical data?

Yes. So the SAD/MAD data in healthy volunteers from the Phase Ia, we presented those this past June. We actually moved through that study very quickly even though we had over 150 subjects on that study. And what we learned from that study is that we can fully, completely degrade STAT6 in blood and skin in relatively low doses, doses as low as 50 to 200 milligrams a day, complete degradation. That degradation was associated with full pathway blockade of the IL-413 pathway, which we showed through impact on circulating biomarkers like TARC and eotaxin. And importantly, it was very safe and well tolerated. The MAD consisted of 14 daily doses of drug and the safety profile was essentially indistinguishable from placebo.

Got it. And then, of course, you're going to be moving 2 doses for the Phase Ib trial right now. Could you maybe just -- just help us understand what are the expectations for the data readout in atopic dermatitis for -- in December and set some expectation around what should we be looking for in the data set?

Yes. So maybe starting with like what are our objectives -- what are our objectives for Phase Ib. So the main objectives for doing a relatively small uncontrolled study was, number one, to show translation of safety and PD from healthy volunteers to patients. That was very important for us for the study. Number two was through that translation of PK and PD to confirm the doses that we were going to be selecting for the Phase IIb dose range finding study. And third, to really show hopefully a dupi-like impact on TH2 biomarkers, both in the blood and in skin with 28 days of dosing, which was the duration of the Phase Ib. And then finally, to also be able to show potential impact on a variety of different clinical endpoints in AD even in the absence of a placebo control, we think this was an opportunity for us to be able to show initial activity. To your point around the doses, we initially started off with 1 dose that was selected based on our Phase Ia data. You may recall that at doses of 50 to 200 milligrams in Phase Ia, we saw complete degradation in blood and skin. So we bought one of those doses into the Phase Ib. And after enrolling 10 patients and doing that briskly, we felt we saw enough data to allow us to actually bring a second dose into Phase Ib. So we could show translation across 2 different dose levels. The aim was not for us in Phase Ib to show dose response or to make up with the second dose, any deficits we were seeing on safety or efficacy with the first dose. It was really just to further strengthen the translational database from healthy patients and then further confirm and give us even that much more confidence in the doses that we were bringing into the Phase IIb dose range finding study.

Got it. And on those 2 doses, what sort of STAT6 target degradation should we be expecting on those 2 doses. What we should be looking for?

Well, I think our aim was to bring in doses that would be active, obviously, highly active. For the first dose, as I mentioned, that dose was chosen from the 50 to 200-milligram range. We haven't really given guidance yet into what the second dose was, and we'll make that information available when we actually present the data in December. But again, I think the aim was to be able to sort of translation across 2 different dose levels. If we move to the Phase IIb dose range finding study, where we've already initiated that one in AD. This quarter, we just announced initiation of that Phase IIb study. We have 3 different dose groups and placebo. And what we've said about those 3 different dose groups is that it sort of will give us a sort of pharmacologically active and clinically active dose, a higher dose that would be super pharmacologic and then a lower dose that would be sort of maybe submaximal. And that's the sort of dose range finding that we want to do within a Phase IIb. What we have said about those doses, even though we don't plan on revealing what those doses are for the Phase IIb, we have said that those will be -- those were chosen based on the doses that we looked at in the Phase Ia healthy volunteer study.

Got it. And then just going to the specifics around the endpoints. I know we should be looking at biomarker data like TARC reduction. So could you help us understand what level of TARC reduction would be considered meaningful in your opinion?

Yes. I think TARC is a helpful biomarker to look at in AD. Prior studies with dupilumab have shown greatly elevated TARC levels in AD patients. And in that context, dupilumab have shown anywhere from 70% to 80% reduction of TARC as early as 28 days, again, keeping in mind that our Phase Ib study is 28 days duration. Interestingly, if you look at some of the other dupi studies and other diseases like asthma and EoE, where the baseline levels are not as high as they are in AD, you see less of a reduction, reductions that are more in the 35%, 40%, 45% range, which is what has been seen in healthy volunteers as well. So I think the expectation is that if baseline levels are high as they were in the prior dupi studies, then one should be able to see 70%, 80% reduction of a TARC biomarker even at 28 days. So we've set that as the ballpark that we'd like to be able to see for KT-621 in our Phase Ib.

Got it. And besides TARC, of course, you're going to be potentially showing some clinical endpoints like EASI also in pruritus. Maybe just help us understand some of the expectations for what kind of data readout should we expect in terms of what we consider clinically meaningful?

Yes. I think if one hearkens again back to the DUPIXENT data and going back to, say, the Phase III SOLO1, SOLO2 studies, you can take a look at what they saw at 28 days for changes in EASI and changes in NRS pruritus and get a sense for that's sort of the ballpark that we'd like to be in Phase Ib. When we think about aspirationally where we'd like to be with regard to activity for 621, we believe that the biology and the preclinical data in the Phase Ia healthy volunteer data point to the potential for this drug to be dupi like, and so that's the reason why we'd like to see impact on endpoints such as EASI and NRS pruritus, and even in Phase Ib in the absence of a placebo control that are within the ballpark of what dupi saw at 28 days in their studies.

Got it. Okay. And so then for that Phase IIb trial, you're planning to start in the fourth quarter in AD, you just show us over a quick overview of the clinical trial design?

Sure. So that particular study, which has already been initiated, it's a 200-patient study in moderate to severe AD, typical 16-week duration, primary endpoint, percent change in EASI over 16 weeks. The study also has a 52-week open-label extension period after completion of the 6-week placebo-controlled period. As I mentioned, 3 dose levels, along with placebo. And again, in addition to EASI looking at, not just EASI as a continuous variable, but also looking at EASI-50, EASI-75, looking at pruritus NRS, the IgA, all the typical end points that you would see in an AD study.

Got it. Got it. And how should we think about translation from the AD study into other derm or [indiscernible] indications such as PN, EoE, [indiscernible] ?

I think it's a great question. Our -- currently, our development plan is an accelerated plan where we -- the centerpiece are really 2 Phase IIb studies. We call them sentinel Phase IIb studies, right, one in AD, which has already begun and the second in moderate to severe in asthma, that will be starting in Q1 of next year. Both of those Phase IIb studies actually will be testing the same 3 dose levels of KT-621. Ideally, what we'd like to have happen is for the AD study, the Phase III dose that comes out of that Phase IIb study could be used not just in the Phase III study in AD, but also in other skin indications where dupi has been active and approved as well as in GI indications like EoE. So rather than having to do additional Phase IIb studies, we would go directly to Phase III studies across those other indications. This, of course, still requires regulatory buy-in, but we think that's a reasonable approach. And likewise, for the Phase IIb asthma study, the Phase III dose that comes out of there could be used not just for moving ahead with the Phase III study in asthma, but then also going into COPD, for example, or CRS with nasal polyps, other respiratory diseases where dupi is gone. And also going in and potentially parallel tracking or staggering additional Phase III programs there, again, without having to do any additional Phase IIb studies.

Got it. Can you just remind us how big is the AD market overall?

Well, the AD market is quite large. I mean there are literally tens of millions of patients, and in the U.S. and in Europe and elsewhere in Asia. It's important to remember also that this is a disease that affects children, very young children, adolescents as well as adults. So it really is a very sizable population. If you look at the moderate to severe segment of patients with AD, what's really striking is that only about 1% to 2% of those patients are actually getting access right now to dupilumab, which is a highly successful active, well-tolerated drug. So that means is that there are the other 97%, 98% of patients with moderate to severe disease, and we're talking tens of millions of patients, right, who if we have an oral drug that were potentially as safe and active as dupi, you can imagine that, that could then be accessed by that many more patients, it can really be a drug that now transforms the lives of many more patients, both young children, adolescents as well as adults.

Got it. Got it. Great. Now let's switch gears and talk about the -- your second program, which is the IRF5, the KT-579 program. We saw some encouraging preclinical data at ARC recently. Can you just maybe share a quick overview of the mechanism and biology of IRF5 and how do you think you could complement the STAT6 program?

Yes, the IRF5 program is another very exciting program for us. KT-579 is the name of that program. And again, like STAT6, it exemplifies, we believe, marrying our platform technology to ideal targets and pathways where we think we can really have a transformational drug that can reach millions of patients with high unmet need. IRF5 has been of great interest for years for both big pharma and biotech because it mediates signaling through B cells. It's involved in B cell activation and autoantibody production. It's involved in controlling type 1 interferon production. And it's involved in controlling the production of multiple different pro-inflammatory cytokines. So it affects B cells, monocytes, plasmacytoid dendritic cells, and even neutrophils. And it's essentially activated through all the different toll-like receptors and other innate immune receptors. IRF5 is unique in that, its expression is restricted just to those types of immune cells that I just described. And it's also usually just activated in the setting of sort of pathologic inflammation. So it's a target that's been of great interest because it can affect all these pathways that have been validated indirectly by other drugs that are targeting type 1 interferon receptors, targeting pro-inflammatory cytokines, targeting B cells, but you could have it all in one drug targeting IRF5. But it's been very difficult to drug. It's a transcription factor. There are multiple IRFs. And even IRF5 has multiple isoforms. So finding a drug that is highly selective for IRF5 and completely block its activity has been very difficult. But now we have a degrader that can do just that. We have a degrader that's highly selective for IRF5, highly potent, can be dosed once orally daily. And we have these preclinical data that you referred to, David, that we presented at ACR recently, where in 2 different mouse models of lupus, we see very strong activity that's equivalent to or usually better than other approved drugs or active drugs as well as data in rheumatoid arthritis. And what's attractive about this target is that there's very strong genetic association between IRF5 polymorphisms and susceptibility to lupus, to inflammatory bowel disease, to RA and to other type 1 interferons like Sjögren's and systemic sclerosis. So now having these powerful data in animal models of SLE and RA just give us further confidence in the potential of this drug across those various indications. And so our plan right now is we've completed IND-enabling studies for this program, and we plan on initiating Phase I in healthy volunteers early next year and to have data readout sometime next year as well. And then following that, we will then be moving into our first patient studies.

Yes. This seems like this is [indiscernible] very wide in terms of applicability. So I'm curious in terms of your thoughts around what will be some of the leading indications you were thinking of?

I think lupus is certainly at the top of the list for us, given the very -- it probably has the strongest genetic association with IRF5. Obviously, a huge unmet need, very little in the way of oral active drugs in lupus, and the strength of our animal model data, I think lupus is definitely sort of high in our list. But I think at the same time, there are also these very interesting genetic associations with IBD and RA. We already have this animal model data in RA, which is also looking very positive. So I think lupus certainly probably at the top of our list, but multiple other indications that I think we're still working on how we might prioritize those, whether there are other type 1 interferonopathies or whether it's IBD or RA, I think that's still a work in progress that we'll sort of share more on that as we get further along in our thinking.

Yes. So then maybe help us understand some of the expectations then from healthy volunteer data, what are you looking for to actually to determine that you're -- that you want to move into certain indications?

Well, I think certainly, in terms of Phase I healthy volunteer study, I think as we get closer to starting that study, we can provide more information on it. It will be certainly sort of a SAD/MAD standard, and you've seen sort of our SAD/MAD healthy volunteer studies now across multiple programs. For us, it's going to be important to be able to show that we can strongly degrade IRF5 in blood and then at least another sort of tissue, such as skin, for example, which we can look at in healthy volunteers, showing safety, showing we can do this and get deep degradation 90%, 95% or greater at reasonable doses. So those are among the probably most important sort of biomarkers that we'll be looking at in that Phase I study.

Got it. That's helpful. Great. And then moving on to your IRAK4 degrader, KT-485. So when you look at -- [indiscernible] of the program is being partnered with Sanofi, and Sanofi has prioritized next-generation IRAK4 degrader, the 485 over the first-generation degrader 474 due to some subclinical QTc issues. So I'm just curious, could you share some detail around what have you seen that caused the QTc polongation?

Yes, it's a good question. With KT-474, we did see this subclinical QTc prolongation, and we investigated that very thoroughly. What we can say is that, that was really very compound specific. It was not at all any sort of degrader class effect. It had nothing to do with actual on-target IRAK4 degradation. It was very specific to that particular compound. And we've learned a lot from that. We've learned preclinically how we can avoid having any hERG impact, having any QT effect. We now use nonhuman primates cardiovascular studies in order to make sure that any compounds that we're bringing into the clinic will be fully derisked around having any QTc prolongation. And so I think all those learnings from 474 have been applied not just to 485 obviously, which, as you mentioned, is why Sanofi is now so interested in moving that forward in place of 474, but also applies to all of our other programs, including STAT6, IRF5 and all the other programs to come.

Yes. And just to kind of follow up on that. What kind of learning have you -- were you able to gather out of that 485 or 474 that you can apply to other degraders, not only for your existing programs, but also down the road?

Yes. I think it's really learning. It's all about chemistry and learning what is it about chemistry of any compound that might contribute to having an effect on hERG channels in your earliest preclinical work. And even when you're done avoiding having compounds that have any impact on hERG, you wanted them be even more reassured by putting those compounds into cardiovascular studies in monkey. It turns out that monkey is really more predictive than dog in whether you're going to have any QT prolongation with the compound. So knowing that we can now not just used in vitro hERG as a way to avoid compounds that can cause QT prolongation, but now this added step of now putting those compounds into nonhuman primates, and showing definitively there that there's no QT effect with multi-dosing, I think that really strongly derisks seeing this sort of an issue with any future compounds.

Got it. Great. Okay. I think we're almost out of time. So maybe just one last question, Jared, what's like the next catalysts over the next 12 to 18 months that we should watch for?

So I think, obviously, for December, our plan is to present Phase Ib data. That's obviously a very important catalyst. We just recently announced initiation of our Phase IIb AD study. In Q1 of next year, we'll be announcing initiation of our -- of our Phase IIb asthma study. I think further catalyst next year will include Phase I data for KT-579. I think our expectation, although this is beyond our control, this is in Sanofi's control, but the expectation is that Sanofi will be moving 485 into Phase I healthy volunteer trial next year. And our plan is to move at least 1 or 2 new programs into the clinic into our pipeline each year. And I think those will really be the main catalysts. And as I mentioned earlier, with our cash runway that goes through the end of -- the second half of 2028, I think we're also looking at important catalysts in 2027. We've guided that the Phase IIb AD study will complete by the middle of 2027. So that will be another important catalyst. And that cash runway, I think, gets us through these Phase IIb studies, the startup of potential Phase III studies for AD and asthma as well as key Phase I and Phase II readouts for the IRF5/KT-579 program.

Great. Okay. Well, I think with that, I think we can conclude here. Thank you, everyone, for joining, and thanks for -- Jared for your time coming to UBS conference.

Yes. Thanks for having us here, David, and thanks for the question.