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

Okay. Perfect. Welcome to the Second Day of the BofA Healthcare Conference. I'm Geoff Meacham. I'm the senior biopharma analyst here. We're thrilled to have Kymera with us. And on stage with me is Nello Mainolfi, who is the Founder, President and CEO. I got the name right, right?

Perfect, Geoff. Love it.

So maybe to kick it off, Nello give us just a high-level view here and just talk through kind of targeted protein degradation and kind of where you guys sit?

Excellent. So first, Geoff, thank you for inviting us. This is a great conference. We love being here, and you guys do a really great job. So a protein degradation, it's the only new small molecule-based drug modality of the past really 50 years. It gives us an ability to address the 80% of the drug proteome that we're not able to address with existing modalities, whether it will be small molecules, antibodies, oligo-based therapeutics. So in principle, has the potential to really change how we think about treatment paradigms. So -- and it does at really in the high level with a very simple concept. You use small molecules to bring disease causing protein to the ubiquitin-proteasome system, which is really the disposal mechanisms that are cells used to get rid of proteins. You can do that very selectively, very rationally designed, it's disease-agnostic, tissue-agnostic, target-agnostic, and so really, the -- I would almost say sky is the limit in terms of opportunities. So it's our responsibility, not just an opportunity to deploy against the right type of targets, the right type of diseases, the right type of patients to maximize value for patients first and then for everybody involved.

Perfect. So let's talk about 474. So just walk us for those that may not be as familiar, where you are in the clinic, and then we can talk about the QT thing. We finally think of put that to bed, but.

Yes. No, thanks, Geoff. So maybe I'll just take a moment to highlight. So just concept of protein degradation that we just covered. So Kymera was funded in actually now 7 years ago with the goal of building a commercial stage fully integrated biotech that will fully capitalize on the power and opportunities of the technology. So we have 4 programs in the clinic, 1 in Phase II and 3 in Phase I. So while obviously, we made a lot of progress. We've executed really well. We have a great team. We're still very early versus the promised land of being a company that commercializes its own drugs. But obviously, you have to go through the stages. So it's important that we continue to invest on the right targets, deploy capital against the right opportunities; and b, as I like to say, brutally honest with how we interpret any data that we generate. Our first program, going back to your question, Geoff. Our first program that entered the clinic actually a couple of years ago now is KT-474. It's an IRAK4 selective degrader for a wide variety of autoimmune diseases. So IRAK4 is a central node in the IL TLR pathway and degrading IRAK4 unlike inhibiting the kinase function of IRAK4, there are other companies before us have done gives you the opportunity to fully block the inflammation driven by IL-1 TLR, IL-1 receptor TLR receptor activation. And we've shown preclinically extensively, but now also in Phase I in both healthy volunteers as well as patients with HS hidradenitis suppurativa and AD, atopic dermatitis that blocking -- degrading IRAK4 gives you an opportunity to see meaningful clinical benefit in patients through an ability of full degradation of IRAK4 in blood, substantial degradation in skin and impact on a broad series of cytokines and chemokines. So the program is partnered with Sanofi, who is responsible for Phase II and beyond. And so we are -- have transitioned the program in their hands since December, when they decided to take on the program into Phase II and beyond. And we will announce Phase II start when that happens, as we said also as recently as a few days ago.

Great. And just on the safety tolerability profile looking sort of the more recent kind of updates on the QT thing?

Yes. So this drug has been actually tested in close to 150 subjects in Phase I. It's been in a typically comprehensive Phase I for a lot of reasons, but we also believe that for a new modality, you really have to do a comprehensive job, especially in the early translation. We've demonstrated that the drug is really well tolerated. Is -- again, it's been tested in multiple subjects, both healthy volunteers and patients. There hasn't been any serious adverse events, the only adverse events and being mostly mild in nature like headaches in some case, nausea. And what we've uncovered that Geoff is referring to in the healthy volunteer 14-day study is subclinical non-dose-responsive nonadverse prolongation of QT of, again, slide 10 to 20 milliseconds. We've also seen that when we went into patients and went from 14 days of dosing to 28 days of dosing, we saw that we continued dosing from day 14 to day 28, the -- this, again, subclinical QT prolongation results spontaneously so much that by day 28, the QT was back to baseline. So basically, we've encumbered this subclinical transitory signal, there is only apparent around day 7 and starts going down already again by day 14 and completed resolved by day 28. So while even in the presence of the early understanding, we were under the -- we're working under the assumption that we would have no impact on how we were thinking about development of the drug. Now with the, again, spontaneous resolution, we don't believe this is something that is of any impact on our clients.

Right. Perfect. So Sanofi is going to initiate the HS study. So talk about kind of what does success look like there? And maybe just at a higher level, Nello, talk through kind of how you view the risks of investing in the kind of the I&I space versus hematology, oncology, the -- you have different parameters and different acceptances of safety tolerability?

Yes. I mean I would say that we were the first company in protein degradation to invest outside of oncology within both small and large companies because we believe that -- and we still believe that the future of immunology is small molecules. And right now, it's dominated by antibodies, but the future is small molecules. And in order for the future of immunology to be small molecules, you have to have really active, well-tolerated small molecules. And we saw that the opportunity of this modality to degrade protein and provide unprecedented biology was a way to transform the immunology space. We were in immunology when immunology was obviously fascinating and interesting and large opportunities, but obviously not as hot as it is today where everybody talks about immunology. So we were, let's call it, fortunate enough to think about immunology early in the stage of the company. We don't think about -- we're well aware that it's important to have a pristine profile when your immunology, and we have no reasons to believe that this technology will not allow us to have highly selective well-tolerated drugs. We totally believe that that's doable with protein degradation. And actually, it's a feature of protein degradation, high specificity, high selectivity. And we will continue to invest in both immunology as well as oncology. If you see on our website, on our corporate deck, we have several programs that are preclinical at this stage that are designed to unlock novel immunology mechanisms as well as novel oncology mechanism. But we will continue to do so. We believe we have the know-how, first-in-class know-how in immunology to continue to drive value there. Going back to the question on Sanofi on HS. So as we've disclosed in December, the collaboration, so Sanofi and Kymera have prioritized HS and AD for the first Phase II studies for KT-474, that does not mean that those are the only 2 indications where this drug will be developed. This only means that there are the first 2 indications. We believe that with continued tractability and with continued data, there are many, many other indications that are being actually right now prioritized to eventually develop this drug. As we talked about timing. We know that HS will be the first indication and followed by AD, not in a sequential manner, but in a staggered manner. And so we're excited about generating, again, first-in-class data in a placebo-controlled manner unlike, obviously, the Phase I study that we run.

Yes. HS is a bit more of an unmet need. I wouldn't say atopic derm is not an unmet need of but it's just it's a pretty competitive field at this point, right? How do you think about product differentiation at the Phase II level?

Yes. I mean in HS, so far in the U.S., only HUMIRA is approved, I think it -- there will be more drugs approved probably in the next couple of years in HS. AD, we really have a pretty impressive drug that the Sanofi has had with Regeneron has done a great job developing, which is DUPIXENT that probably will become the #1 drug in the world in the next, I don't know, couple of years. But let's remember that both HUMIRA and HS and I would say even more DUPIXENT, and AD have limited penetration in that patient population. I think DUPIXENT right now, it's around the 8%, it's 6% or 8%. I don't remember exactly. And again, in HS, HUMIRA works, but not as well as we would like. And so there are no small molecules approved with a good safety profile in any of these indications. So the opportunity is to continue to generate data that demonstrate clinical activity, good safety profile. And then I believe we have huge opportunities, both well patients to provide them with a simple oral options to these complex diseases and also, obviously, commercially given the unmet need and the large opportunities. And I don't think -- I think competition is important because patients need alternatives. There is no single drug that will solve any immunology disease as there is no single drug that solves any oncology disease. And so it's about providing a drug that will have patients in their treatment paradigm and allow them to have a convenient and active drug for as long as possible.

Nello, do genetics tell you anything about patient populations that are more at risk from protein degradation, sort of malfunction. When you look across the spectrum, right, of what immunology indications you can go after, usually you see that in oncology?

Yes. Yes. So where does human genetics state in immunology. So this is where immunology will move, right? Will move into patient ratification. I think every company, we included are working to understand and to increase basically probability of success, as we've done in oncology, if you have a responder population, you want to focus on your responder population. It is fair -- especially for IRAK4 where we have a pleiotropic broad anti-inflammatory signature. We probably can be a bit more ambitious in terms of percentage of population that we can serve because we impact so many cytokines and chemokines. IL-17, IL-23 TNF interferon, Th2, Th17 biology. So we have really a broad opportunity. But nonetheless, understanding where the responder population lie is important. I think we know human genetics as point to 2 diseases where some mechanisms are more suited for. And I think TYK2 is a good example of human genetics. IRAK4 has shown strong human genetics on safety and obviously, also human genetics experience in terms of other diseases. We have other programs in our pipeline in immunology that we haven't disclosed that will follow probably much more human genetics and clinical experience than other -- maybe other companies right now. So it's obviously an area that is going to require still a lot of investment. But protein degradation is the closest out of all technologies out there to mirror human genetics than any other technology, I've already said that. So keep an eye on protein degradation in immunology because that's what is going to, I think, really change how we think about treatment paradigms.

Got you. Well, coming up, you guys should have data for 413 and 333, safety and degradation results. So give us some perspective for how do we benchmark this? What does sort of success look like? How do we think about the products in advance?

Yes. So maybe I'll just do a brief history here just to make sure that the communication is clear. So we started these programs, dose escalation in the middle of last year. KT-413 is so-called the IRAKIMiD degrader, degrades IRAK4, Ikaros and Aiolos. And we found that if we degrade IRAK4, Ikaros and Aiolos, we're able to generate a synergistic signature in MYD88 mutant tumors. MYD88 mutant tumors are MYD88-mutant lymphoma, diffuse large B cell lymphoma. About 25% of patients with diffuse large B cell lymphoma have this mutation. About 90% of Waldenström’s patients have this mutation and about 70% of primary CNS lymphoma have this mutation. So it's a sizable well-characterized population. Our dose escalation is in B cell -- broad B cell lymphomas. So we're not selecting for MYD88 mutation. We showed in December the first 2 dose cohorts, dose level 1 and 2. PK/PD and safety. We've said in 2023, we should be able to dose escalate high enough in the active doses, which we believe are dose level 3 and 4 and bring to the study enough patients with MYD88 mutation that by the end of '23 in the, let's say, in the second half of '23, we should be able to evaluate the antitumor activity of degrading IRAK4, Ikaros and Aiolos in MYD88-mutant patients. So the goal for 23 is for us to evaluate the clinical activity. So what does degradation of Ikaros and Aiolos do on MYD88 mutant patients, that's the goal for the year. And what we've said recently and that's the goal that we believe, based on where we are with those levels, where we believe is our active dose levels and the type of patients that we can recruit to the study. Based on these parameters, we believe we should be able to answer that question in the second half of the year. Going back to the question from Geoff, we have a presentation at ICML next month, actually, in June, where we're giving a clinical update on the study focused on where we are on our -- dose cohorts where we [Audio Gap] during the year disclosure, so that if we're able to demonstrate that we're at or close to the clinically active dose and where we are with safety, then it sets up the disclosure later in the year about clinical activity. This is 413. For 333, which is a STAT3 degrader, we have shown also late last year, actually, we showed dose level 1. Also in that particular case, we said that dose level 3 and 4 will be -- we expect them to be clinically active in -- for KT-333 as STAT3 degrader, which is really a broad program, we've seen preclinically that patient -- tumor types that respond to single agent are T-cell lymphomas, especially PTCL, CTCL, also LGL leukemia. And we -- and in solid tumor, we've seen most activity in combination. We've seen with PD-1, and we've seen it also with other agents that we haven't disclosed yet. So in our dose escalation, which is actually open to both solid tumors and heme tumors, the responder population is a subset of heme tumors. So for us to show -- evaluate clinical activity, we need to be at the active doses and then recruit to the study enough patients from CTCL, PTCL, LGL. So also for that reason, we believe that between getting to the active dose and recruiting the right patients, this will be a second half of the year, timing disclosure. But also at ICML we'll update on where we are with the program, where we are with the type of patients that we've seen and also with the PD and safety. So it will be clear that ICML why we're seeing that the disclosure is around clinical activities in the second half of the year. There will be no doubt why we're seeing that. And so speculation about lack of clinical activity, et cetera, will be clarified at that -- at ICML. And I think everything will be clear why we're saying this is going to be a second half of the year. Sorry, this was a long answer.