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

Hi, everyone. Welcome back to Day 4 of the 2021 Credit Suisse Healthcare Conference. I'm Judah Frommer. I cover biotech here at CS, and we're happy to have Kymera with us. They'll start out with a presentation, and then we'll have some time for Q&A after. So Nello, why don't I pass it over to you?

Thanks, Judah. So thanks for the invitation. Great to be here. So what I thought I would do, just go through some slides maybe for the first 20, 25 minutes, and then we can leave time for questions. The team is online as well, if needed. So let me put the slides. So hopefully, that's visible to the audience. So again, thanks for the invite. The goal today is just over a bit of history and why Kymera was founded, but then spend most of the time providing an update on what we've done really in the past, I would say a few weeks, if not months, and what we're expecting to see in the next few weeks and months. And since a lot has happened, I think it's a great opportunity to do this presentation. And then the usual fireside chat so that we have the opportunity to try and make sure everybody is on the same page. So on the slide that you see on the screen, this is just a reminder of why we were founded. The opportunity that eventually will lead to transformative therapy is grounded into a really technical but profound opportunity, which is expanding the druggable proteome. All the technologies that we've been using as an industry have been amazing in their impact but still limited to dragging about 15% to 20% of the characterized proteome. And so there is clearly is the need of a technology that can combine, let's say, the power of these genetic like medicines with the flexibility of small molecule. And so this is really the place that targeted proteome degradation has taken today in the spectrum of modalities. And I think this is why we believe that this technology has the potential to change treatment paradigms across all disease areas. I think it would be -- I just want to say it clearly, it would be silly for me to say that protein degradation is going to conquer all the undruggable space. But I think I believe strongly that protein degradation is positioned as the most promising new modality out there. A reminder about the company, we -- again, the foundational hypothesis and thesis, I should say, was around expanding the druggable proteome using targeted protein degradation. Our vision is to take the technology and the opportunity and build a fully integrated business that will eventually take this technology into commercial stage and having a disease-agnostic, technology-agnostic protein degrading medicine company with global reach in the next few years. And then actually, we'll use the R&D Day, which we have announced yesterday will be on December 16, to actually tell you more about what that looks like. We believe in the growth and the continue to be a strong independent company, but we also understand that leveraging the biopharma industry is critical for a small company that we still are to continue to grow organically and maybe also in a derisked manner. So our collaboration with GSK, Vertex and Sanofi, which are all very different -- one is technology based, one is discovery based, one is clinical and commercial based, are an example of how we're looking at those opportunities. Internally, our pipeline is focused on oncology and immunology. Thanks to our collaborations, we actually work on 5 other different diseases. And I think it's fair to say that at this point, we are already very much disease-agnostic proteome degradation company. Kymera prouds itself, and I'm very proud for the work that the team has done to accomplish a series of firsts for not just the company, but I would say for targeted proteome degradation as a field. We were the first company to demonstrate proof of mechanism and proof of biology in a placebo-controlled randomized Phase I study with our first-in-class KT-474 IRAK4 degrader. And recently, we also announced actually yesterday that our KT-333, our STAT3 degrader, is the first heterobifunctional molecule that is going after an undrugged transcription factor into the clinic. We just announced IND clearance from FDA that happened recently. And again, we announced it yesterday. We expect to have 3 clinical stage programs by the end of the year, including, as I mentioned, both immunology and oncology. Our discovery platform that we will cover more about during the R&D Day, is built in a way where we expect, going forward beyond 2021, to have at least 1 IND per year. And we are well positioned in terms of cash. We closed the follow-on financing in early July, and that takes us to about $610 million on our balance sheet, which is critical for our stage of growth, but also gives us the flexibility to really plan well. And this cash will allow us to get into 2025 according to our current plans. Again, just the slides allows me to just give a brief overview, and then I'll speed up the presentation of where we are as a company. We believe KT-474, our IRAK4 degrader, is placed to be potentially a best-in-class small molecule oral anti-inflammatory drug based on the preclinical data on clinical validation with other mechanisms as well as our early clinical data. And so we're excited about having shown the SAD data recently in a conference and excited to share the MAD data in December in the R&D Day. The 2 oncology program, KT-413, which for us is the first targeted therapy in lymphoma, is also on track to have IND cleared and initiating clinical activities before the end of the year. This is a program that, again, we're excited about even our ability to determine the responder population in the lymphoma subset. STAT3, which I just mentioned, has been cleared to proceed. And we were in -- we're ramping up our clinical activities to potentially initiate clinical trials before the end of the year and dosing shortly thereafter. This program, as again, we'll see probably a bit more during the R&D Day in December. We have well-defined clinical translational hypotheses in liquid tumors. We have a SITC presentation tomorrow where we'll go a bit deeper into our immuno-oncology, solid tumor indication hypothesis. And then we'll talk about all the immune and fibrotic businesses later in the year. So this is another potential franchise the way that Kymera likes to build our programs. I will also say that -- and I promise you it's the last time I mention the R&D Day, we will be discussing our next development program. This is a program that is going into IND-enabling studies in December. And this is going to be a new pathway, a new target, that Kymera at this point, I think, is the only protein degradation company pursuing that particular program. I also want to highlight that -- I won't have the time today, so I just want to highlight it now. We have talked extensively about our E3 Ligase platform. And I will highlight during the R&D Day -- actually, one of my colleagues will some really exciting data on how we can be sparing particular tissues from particular pharmacology by using E3 ligases that have selected or restricted expression profile. So look out for that again for the R&D Day on December 16. So just briefly, what is Kymera platform and what is protein degradation? I think many people understand what the technology is about, but very briefly, this is a technology that uses bispecific hetero-bifunctional molecule to co-op the cellular machinery that is responsible for proteome homeless and degradation of cellular proteins and bringing disease cars in protein to the cellular machinery for targeted degradation. So it's a highly specific highly efficient. And I would say that it's probably, at this point, the most powerful target-agnostic, disease-agnostic drug modality that I can think of in 2021. Kymera's platform, which again, I won't have the time to go into the details of today, but has been an extensive investment for the past, I would say, at least 4 years, with the goal of continuing this investment as a mean to build Kymera into -- a long investment into, again, making Kymera a fully integrated business with an eye of continuous innovation. We want to innovate ourselves rather than have to make arguments that we are better than x or y new company. We want to do internal innovation constantly. And so some of the areas that we've invested heavily on our, as I mentioned, E3 ligase discovery. We want to be able to target a new class of target for which sparing particular tissues or degrading just in particular tissues will provide clinical opportunities that were not present with any other technologies before. And as I mentioned, you'll see examples of this concept in vivo in a presentation at the R&D Day, we hope for that program to be in development already next year. And we are also a company that believes in TPD and quantitative pharmacology. And I think our Phase I. [Audio Gap] so the depth and breadth and [indiscernible] of how we think about developing these drugs, as well as you see later in the year also our investment into chemistry. And what I want to also preview for everybody, you will hear from us how Kymera is investing in other technologies that are still under the umbrella of protein degradation in a very differentiated way versus also our peers in both small and large companies in this space. So going into our program. So the first one is KT-474. I don't want to spend too much time on this slide. But just as a reminder, this is one of the most validated pathway in native immunity responsible for signaling of a series of cytokines IL-1 alpha, beta, 18, 33, 36, but also the STAT 3 is responsible for the secretion of a series of cytokines like TNF alpha, Interferon IL-1 beta, 6, 8, 10, 12, 17, 20, 23. So I don't think it's an overstatement for us to say that this is probably one of the most [indiscernible], broad inflammation pathway out there. And our IRAK4 program, we believe, has the potential to be the broader stacking small molecule anti-inflammatory agent. So where is the confidence coming from in us investing and now developing such a program. So we know that there are antibodies to cytokines, they signaled to this pathway. They are captured here on the right in the middle of the slide that have shown both proof of concept in the clinic, some of them have been approved. We know that there is -- the closest validation is an IRAK4 small molecule inhibitor that has been developed from Pfizer which is really a suboptimal engager of this pathway that has shown in array a proof of concept -- We also have human genetics derisking, showing that humans with IRAK4 null mutation on healthy adults, we know that IRAK4 functions only through the kinase domain, but also through scaffolding domain, which is responsible for maintaining signaling of the contacts. And so we believe that a IRAK4 degrader has the potential to achieve this broad well-tolerated anti-inflammatory effect that is superior to both cytokine as well -- blockers as well as small molecule inhibitors. So you'll not be surprised that such a mechanism has a really broad opportunity set in TH1, TH17 biology as well as TH2. And we are working with Sanofi. This is a program that we're working together with Sanofi in the clinic. Kymera now is driving the clinical development. Sanofi will drive Phase II and beyond. And we are selecting indications in this process, right now prioritizing the ones that you see both in this slide. And you see all these indications that have strong both human genetics as well as pathway proof-of-concept already provide a really huge commercial potential, as you see captured by the numbers of the slide. And obviously, this is also with the backdrop of the limitation of current therapies. If you think about anticytokines or receptor antibodies that target only a small subset of the cytokines that we can target, as you'll see in a couple of minutes, and also, as we said, small molecules, anti-inflammatory agents at this point in time are quite limited. We've talked about the IRAK4 small molecule inhibitors. Obviously, we can talk about JAK inhibitors with the characterized safety challenges. So just a reminder, I won't go into a lot of preclinical data, but this data that you see on this slide are the most important. On the left, this is a proteomics volcano plot that shows on the top left, down regulated proteins; on the top right, up regulated protein. KT-474, only degrades one protein, which is IRAK4. On the right, showing that if you have strong inflammatory conditions, and these are in our lab created by stimulating human immune cells with LPS and IL-1 beta, and then we look at a downstream secreted cytokine like IL-6 you can see that using a degrader has the ability to block cytokine production in a way that is drastically superior than, again, even the clinically active Pfizer molecule, in green on this slide. So going through -- sorry, I skipped this slide here. Clinical slides very, very quickly. We have our Phase I study, a very comprehensive data set that we're trying to build for many, many reasons, not only because this is going in immunology, but we believe that we have a responsibility as the company that we believe is doing this at the really high level of characterizing these mechanisms, especially outside of oncology, really, really well. So we have a SAD portion single ascending dose study where we look at PK, PD as a mean of knockdown of target as well as proximal biomarker; MAD, where we're looking and again, PK, PD; and a more extensive subset of biomarkers. And then we also have a cohort of patients early next year, where we're going to ask the question, is the PK, PD proximal biomarker profile conserved as one transitions from healthy volunteers to patients. So just to give you very briefly in terms of PK, this is a really well-behaved molecule consistent PK, dose-dependent increase of exposure going from 25 mg all the way to 1,000 mg per kg. At that point and beyond, we've reached a plateau of exposure. What's more important though is that we are able to reach at of degradation that happens much earlier, in fact, as soon as we reach about 600 mg per kg, we're able to reach maximal degradation. And you see in this plot that not only we see very profound degredation touches maximal, which is for us 95% or above, which is really the limit of our assays, but it's also prolonged for several days. You see on the left here or on the right, that we maintain sustained degradation up to 6 days and then there is recovery on day 15. So really profound degradation, dose responsive and that is extended over time. But if you take one time point, we tend to choose the navy here. So the point of maximum degradation, and you see the nice dose response. And then once you get to about 600 mg total dose you'll see that you reach maximal degradation, and then between 600 and 1,600, you see conserved numbers. And that's, again, driven by the fact that we're not really able to read much more than that I think this is probably the most important slide. We've reported some of these PD data before the the cytokine is what has been reported recently a couple of weeks ago, and this day has very significant. So if we look at the kind of a years anywhere between 24 and 48 hours, that doses in which we reach concentration, they lead to 85% degradation or more, we see this really profound, really broad anti-inflammatory effect. We see if we activate this blood -- this is whole blood, so this is not just 1 immune cell type, but the whole immune cell type that is present in whole blood. If you activate ex vivo after we take the blood from subjects -- from healthy subjects, and then we look at our ability to block that signaling, you see we're able to block with both activation of LPS, which is TLR4, R848, which TLR7 and 8, we block a broad variety of cytokines, up to -- up to 97%. So very broad, very profound anti-inflamnary effect. And we wanted to contextualize it with other regions that have been tested in a Phase I or even a Phase II study using ex vivo cytokines readout. And believe it or not, the number of drugs that have been tested this way are actually quite limited. So you could see besides our IRAK4 degrader, we have a nonselective IRAK4 inhibitor, we have an MK2 inhibitor, [indiscernible] for [ 50 ] compound. We have a PDE inhibitor. We have an [indiscernible] as well as T cell activation [indiscernible] from J&J. And just to give you a sense, I probably shouldn't have read all of those. But to give you a sense that the overall anti-inflammatory profile is profoundly broader with our IRAK4 agent than it is with any other agent out there that has been tested using this ex vivo assay. In terms of safety, this is as benign as we could have hoped for. I just want to remind the human genetics point to a really none -- a very, very safe profile, really healthy adults. Preclinically, we really have seen an exceptionally clean profile. So we're not surprised that this continues to be this way. We saw no serious adverse events. We did see some possibly or probably score treatment-related adverse events, these are nondose responsive. Again, we're seeing in SAD5 and 6, not a SAD7, which is the top dose. They're also set limiting and cleared on their own, and in a way, usually benign in nature. So again, we feel -- and actually something I want to remind, these are blinded safety studies. So we don't know if this apply to treatment, apply to placebo, apply to both. So -- But regardless, we feel this is as good of the profile as ones in the Phase I study. So this gives us, again, continued confidence in this drug. So I will probably briefly skip the summary. I think I've shown you what I've told you, which is really the PD leads to profound degradation that is concerned, almost maximal degradation, going all the way to 96%. This leads to an ex vivo cytokine profile that we believe at this point is best-in-class in terms of both depth and breadth of of activity and the safety is again probably best-in-class in terms of small molecule anti-inflammatory agent with really minimal, if at all, side effects. Reminding you that our MAD study that is ongoing, we will present key data from that study at our R&D Day on December 16. And there, we will be showing, again, safety, PK/PD, which includes IRAK4 level in blood and skin ex vivo cytokines as well as a potentially more distal biomarker like [indiscernible] protein. I will try to move a bit more quickly here. So it's important to highlight the IRAKIMiD program. This is a program that we built, I would say, at the back of our IRAK4 franchise. And our hope and plans were to take an IRAK4 degrader into MYD00- Mutant Lymphoma. We know that this pathway is really a driver of differentiation in a subset of lymphoma cells. We know that MYD88 patients are the ones that have the worst prognosis in lymphoma. And so we wanted to use our know-how as well as chemistry to develop another targeted therapy in this case, [indiscernible] lymphoma. What we learned along the way that IRAK4 selective action on MYD88 lymphoma is insufficient to drive single-agent activity. And we found that combining in a single molecule with the limit would really allow us to generate the synergistic biology that will have still the opportunity to select patients through MYD88 as the key kind of oncogenic mutation. And so this program that has progressed actually quite fast from the early days, we -- the plan is to clear an IND and initiate clinical activities before the end of the year. Just to give you a sense of -- so I like the IRAK4 franchise, selected franchise, which has actually millions of potential patients, in this case, in oncology. This therapy is targeted, which is actually quite an advantage for an area like lymphoma targeted against the MYD88 mutation, both in diffuse large B-cell lymphoma as well as other areas where this mutation is quite prevalent. One can think about Waldenstrom as well as primary CNS lymphoma. So we're excited about actually initiating this clinical trial soon. But we're also keeping an eye preclinically and eventually, if it makes sense clinically in other opportunities on to other opportunities where these pathways and these mechanisms are relevant, and we'll talk about this in the near future. Just a quick reminder that this is a pathway where the synergistic combination of MYD88 and interferon pathway with imidbiology can produce some really profound antitumor effect so much so that we're able to see even in PDX models, food regressions that are durable even after we stopped dosing our drugs. Something that is important to highlight that while we devised this heterobifunctional dual degraders for really building a single agent therapy that would be approved hopefully in an accelerated approval type of strategy. We also have an eye on potential combination. And this is more to also expand both the impact but also to potentially explore earlier line of therapies. And so you see combination of a suboptimal dose of KT-413 in orange with the dose of Rituxan that doesn't drive full regression, leads to this really amazing antitumor activity. The same combination with Rituxan after, let's call it, a refractory preclinical effect here to [indiscernible] also leads to now reinitiating the strong and [Audio Gap]. Again, these are hypothesis is that we want to pursue clinically in terms of combination, and we will do so after we complete the Phase I escalation studies. So that's a brief overview of what the plans are. Dose escalation and MTD expansion initially in diffuse large B-cell lymphoma, or resistant refractory B-cell lymphomas, including DLBCL. And our plan is to dose once every 3 weeks, and this is due to our PK/PD properties of this compound that we've characterized really well in many species, and we plan to showcase initially proof of mechanism and proof of biology in '22 and then early concept from there. The last maybe 5 minutes on Slide 3. Again, I just mentioned we announced the clearance of our IND just yesterday in our quarterly report. This is a pathway and a target that we're very excited about. We're the first company to drug this target fully with a degrader. Again, as I mentioned, this is the first degrader against one of these really hard-to-track transcription factors. We're excited about this pathway because in this target because unlike upstream inhibitors, the biology is actually quite differentiated, although, I would say, broader than what you see with upstream inhibitors. In fact, we've shown activity both in cancer, inflammation and fibrosis. And in cancer, we have a real clean hypothesis in genetically defined STAT3 populations in leukemia lymphomas and these are going to be probably the early focus for us in order to try and accelerate this program towards approval. But we've also shown, and again, we'll show it tomorrow at SITC, some really interesting data in immuno-oncology, and we're pursuing this as a solid tumor opportunity quite aggressively here at Kymera. And also, hopefully, in December, in the R&D Day, we will talk about some of the really exciting data that is emerging in inflammatory fibrosis that I think this path on this target has a really interesting novel hypothesis to pursue. Also I want to remind you all of our molecules, we try our best to develop a highly selective molecule. And real beauty of targeted flooding degradation, especially using this heterobifunctional molecule is the opportunity to build your selectivity profile really, really well, highly specific for the target that you want to go after so to derisk the development, and really avoid the issue of target activity, which unfortunately confirms the development of many drugs. So highly specific for STAT3. We've shown this slide before many times, in tumor-bearing mice where we look at positive ALCL, we've actually generated other data also outside of the of this particular model, Really only once a week dosing for about 3 -- 2 to 3 weeks leads to full cures and then these these tumors don't grow again. This is very unique. This is uniquely shown in tumors that are dependent on this pathway. And as I mentioned, we'll talk more about the impact on other tumor types, for example, in solid tumors. Again, this development parallels to some extent, what we're doing with the KT-413 in terms of timing and it's also in terms of timing of data release next year and beyond. And we will start here in resistant refractory lymphoma and then we'll add solid tumors as we continue to dose escalate and expand actually. And for this program, unlike KT-413, we're there, we do once every 3 weeks. Here, we do weekly dosing. So I just want to also maybe spend just 1 second on this concept. You've seen we have a drug where we dose every day with KT-474. We have a drug that we dose once every 3 weeks with 413. We have a drug that we dose once every week with 333. And I think while hopefully, this is not confusing to you, is just showing how deeply we build and develop our drugs based on their PK/PD properties and their ability to engage the target and how long they engage the target and not trying to force fit dosing paradigm based on preconceived notions of what is done in drug development for all the, let's say, previously used technologies. I think we all have to think about protein degradation as a new modality and applying the drug development principles from small molecule to days one-to-one, I think, misses opportunities. I don't want to spend too much time on this. I've told you what we've already disclosed. For 474 look out, again, in the R&D Day for the MAD day that this is going to be, in my mind, the key derisking event for this program by going forward. But for 413, we'll talk about IND clearance and Phase I initiation, and in 2022, early data for 333. We'll talk about the initiation of the dosing of patients and then early clinical PTPP and then eventually clinical efficacy report as we go through 2022 and beyond. And again, I've talked to you about the R&D Day. This is just captured at the bottom slide. I'll stop here and allow time for some questions. Thank you.

Thanks, Nello. That was a great overview. We have a few minutes here for questions. If anyone in the audience would like to send me an email with a question, you certainly can. Shoot a [indiscernible] creditsuisse.com. I think you wrapped up with STAT3, so maybe we'll just start there. There are a number of STAT3 inhibitors that have entered the clinic. Could you talk about how KT-333 might compare more generally from a mechanism of action perspective to those other ones?

Yes. No, thank you. That's a great question. I think what I said before is that no one is really track STAT3 well. And actually, I will repeat that. There have been molecules that have been either pathway inhibitors or inhibitors or some aspect of state biology. In reality, the only way to drug a protein that doesn't really have just a function, which is obviously what we know is phosphorylation of itself before going into the nucleus, but actually is involved in complexes that are then translocated in the nucleus. The only way to do it in my mind is to actually remove the protein. So I wouldn't say that protein degradation is superior to other modalities that I almost feel like saying probably protein degradation for a target like statutory is the only way to really have full pharmacology from this target. And also it's the only way to do it in a way where you can penetrate tumors, you can act on immune cells in a way that is unbiased versus, for example, other approaches. The only really other approach that I would consider STAT3 targeting is the work that Ionis did with AstraZeneca with an ASO. And again, that drug had some issue with -- sorry. So I think some challenges with tissue distribution. And so I'm not sure that they were able to capture the food potential of STAT3 knockdown with the modality unlike we're doing here with small molecules.

Okay. That makes sense. And then just following up on that, some of the other molecules targeting STAT3 have have had, I would say, some safety signals, nausea, weakness, blood pressure. Anything we should be looking for in terms of you limiting those possible effects?

Yes. So great question. So what we've seen, again, I think we have a highly specific as you've seen mechanism here. What we've seen is this molecule is really well tolerated at the doses in which we see this really profound dermatology. So we're going into the clinic with a high degree of confidence. Will there be some signs if you go in super pharmacological doses and side effects probably. But I think our goal is and our confidence in translating this preclinical efficacy into the clinic is that we would stay in areas where we know these therapies are quite well tolerated.

Okay. That makes a lot of sense. And I think we are bumping up against time, so we're going to have to stop it there, but we very much appreciate the presentation and your participation.

All right. Thanks. Thanks for the invitation.

Thank you.