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

Hi. Good afternoon, everyone. I'm Ellie Merle. I'm one of the biotech analysts here at UBS. Very happy to have Kymera Therapeutics here with us today presenting as part of the UBS Targeted Protein Degradation Day. Joining us from Kymera is Nello Mainolfi, President and Chief Executive Officer. Nello, thank you so much for making the time. Very timely, we can discuss the latest update with 474, which I think is exciting.

But maybe just to kick it off, can you give us an overview of your protein degradation platform and discovery capabilities? And given there's so many companies in the space, I guess, what aspects of your platform and technology do you believe are unique and differentiated versus other companies?

Yes. Thanks, Ellie, for having us. I guess, it's good to be back to 2020 with the Zoom calls. But it's all good. Thanks for doing this day focused on protein degradation, which I think deserves to have a platform that allows you to go into new nuances of strategies, technologies, teams and people. So I'm really glad you're doing this. So to answer your question, so first of all, we founded the company in 2016 with the goal of using TPD to unlock a whole new generation of targets. We've been fortunate that we've derisked and validated so many pathways, so much biology, so many targets. But I think the technologies have lagged behind. If you look at many technologies that we've developed as an industry in the past 10, 15 years, they all have big limitations, whether it's getting into the cell for biologics, for antibodies or getting the right delivery for oligo-based therapeutics. What we saw with TPD was the opportunity to go after targets that have been undrugged or poorly drugged. And so I would say that the main -- I would start with the main -- the thing that is very unique about Kymera, I would say it's our target selection strategy. We have taken the concept of protein degradation as a validated therapeutic modality when we started the company. We didn't feel the need to develop programs to validate the technology. We felt the need to develop programs to bring innovative medicines to patients. And so our target selection has been focused on targets that have been undrugged, poorly drugged, where protein degradation is either the only or the best way to go after. And if you look at IRAK4, with an evolving story, we were the first companies to go after a target that a small molecule that had gone and failed in the clinic, but where we believe, through data, that protein degradation would be the modality to unlock the value of those targets and of this particular -- in this particular pathway. If you look at our commitment to the STAT protein, STAT3 and more recently STAT6, targets that have been undrugged in the industry for decades with fully validated biology, and we've committed to unlocking the value of those targets. And obviously, I can go on and on. So I think that is a key unique aspect of what we do. Another aspect is our ability to develop chemistry for this difficult-to-drug targets. All the chemical matter that we use at Kymera is developed internally. We don't use the literature, small molecule binders or inhibitors to target our target classes. We develop them internally through a -- always evolving and always getting more sophisticated at finding approaches. If you see behind me, this is a cryo-EM structure of KT-333 with STAT3, and VHL as the E3 ligase. We have a picture -- in fact, the other one in the background, there's another version on this side is things that I can show you. But we have ternary complex structures of every program in our pipeline and in our discovery engine, which speaks to the nuances and the sophistication of our approach to develop these first-in-class degraders. And our commitment to doing translational work, I think, hopefully, you'll agree with me that all the programs that Kymera has taken into the clinic and also in this space, I think we're ahead of the -- in the industry. We've taken 4 programs in the clinic in less than [ 4 ] years since 2020, since we became a public company. And all of our programs have translated with a high degree of fidelity in terms of PK, PD, safety and efficacy. So those are the key pillars of -- I think that makes, I believe, Kymera a very unique company, not only in the degrader space, but I would say, in biotech.

Absolutely. You certainly have moved at quite a rapid pace of bringing new degraders for novel targets into the clinic. What should we expect in terms of that rate going forward? I guess like every JPMorgan, maybe we'll learn some new targets?

So we have an internal commitment to have at least one new IND per year with a new molecular entity. And we've been on track on an average since we set out this goal, which was around 2020. So you should expect at least one new IND per year. In some years, we'll have probably many more than one; maybe in some years, less. But generally, I would expect next year, probably not around JPMorgan, but a bit later, we plan to disclose a new program that would be a new addition to our pipeline. And we expect those disclosures to be consistent year after year.

Great. Well, I could certainly ask you about your platform all day. But for the sake of time, I'll move to IRAK4. Can you walk us through this latest update? And maybe specifically, like what was learned in this interim analysis?

Yes. So maybe just to take a step back, so if you look at the existing study design, at least what's on clinical trial [ GABA ] on our website, let's use HS as an example. You see that there was -- there still is, up to today, 1 dose group and 1 placebo group. I think for people that follow drug development in general, you would expect that before going into Phase III, you would have required to likely run a dose-ranging study. And so the update, when we say we're expanding the study, the current study, to accelerate the development pipeline, what we actually mean is that we expand the existing study to add more doses so that this is the only Phase II study before a Phase III. And so the overall timelines are positively impacted in a dramatic way. Although obviously, the current study is expanded, it probably will take longer to complete. So that's maybe a bit of the backdrop. What I will add to your question, obviously, I can't go into the details of what was seen or not seen, but the only thing I can say is that Sanofi elected to run an interim analysis of the data, of safety and efficacy. This is not uncommon for a company, especially in pharma, to run an interim analysis to also make investment decisions. And so we're happy that this interim analysis look at the data has led to an investment -- further investment decision into the program.

Philosophically, these types of interim analyses, should we think of them as having maybe a higher bar? Or like historically, some interims will be safer futility, others might be -- you've shown exceptional efficacy. Can you characterize sort of where this falls on that spectrum?

Again, I don't want to upset our partners. It's not -- there's not much I can say. What I will say is that there was a clear bar that Sanofi had questions around they wanted to clear, and it looks like based on their decision to expand the investment that [ bar ] was clear.

Okay. Maybe I'll ask the same question in another way. I guess, what's your like view on the likelihood of success? And maybe kind of like how is your confidence now in IRAK4 disease biology and AD and HS relative to a couple of weeks ago?

I mean, as you know, I've always been a big fan -- a big champion of this program, not just because I'm the CEO of Kymera but also because I actually started this program in 2017 because we and I believe that this could be a cornerstone of small-molecule orals in inflammation, given the breadth of the mechanism. Obviously, we cannot guarantee success, but I have a high degree of confidence that this molecule and this target will be relevant in a broad variety of diseases. And the recent data only continues to support my confidence.

In broad strokes, I guess, can you characterize the changes, so it seems like additional dose levels? Anything else that you can talk about in terms of the changes in the study expansion we can expect?

Yes. Hopefully, we'll see the amendments on clinical [ dry dock ] of -- relatively soon enough. And at that point, we'll be able to add more color. The only thing I think we align with Sanofi that we'd be able to comment on is the fact that the real spirit of the expansion is adding more doses. And that's what's going to change. That's going to be the major change.

Understood. Maybe turning to the disease biology. What gives you confidence in IRAK4?

Well, I think it goes back to the pathway. When we talk about Kymera target selection, the mantras is that we like to go after targets that have not been drugged or drugged well, like IRAK4, in pathways that have had a big degree of validation, sorry. And so going to the pathway degree of validation that our drugs that are approved, that target upstream cytokine, so IL-1 family cytokine, IL-1, IL-18, 33 and 36, these are cytokines that must signal through the myddosome complex and IRAK4. TLR, it's a whole other area as well. And we have a plethora of positive data looking at upstream biologics. If you look at the IL-1a, ß biologics from AbbVie, they had some really impressive data in HS in a Phase II study in TNF alpha refractory patients. We've seen encouraging data from the IL-33 in asthma, in respiratory diseases. We've seen other data in [ RA ] in gout, in macrophage activation syndrome, which is a smaller disease. So we have a series of validating data set in Phase II and Phase III with single cytokine blockers. So it's only pretty rational, this is why [ all this ] study wasn't a big bet. It's only rational that if you have a drug that blocks the cytokines downstream of them, so you have a potential to have the activity of the combined IL-1 family cytokine blockers, it's only rationale that this drug should work. Now obviously, the drug is only going to be as good as its ability to block the pathway, the way that we believe it needs to be blocked to have the combined activity of these biologics. And if you look at our data in Phase I, we degrade IRAK4 fully in [ blood ] robustly in the skin. We change cytokine, [ systemic clearing ] the skin. We have early data in patients with some impressive impact on paying [ providers ] and then scores in HS, if you look at AN count or high score 50 or EASI scores in AD. So all the data is pointing to this drug being really active. So that's where the confidence is coming from.

Are you considering starting a study in an additional indication prior to getting the AD and HS Phase II data?

I'm definitely considering. The question is whether Sanofi is considering it. So all I can say is that -- it was a good question, sorry for throwing it to you in there. We have discussed the [ length ] with our partner, and there is a team, a combined team, that has prioritized a series of indications. At this point, it's really after Sanofi to make that decision. And we -- to be honest, we've been so focused on this discussion of recent time around the interim analysis and the expansion of the study that we really haven't had the opportunity to even ask them this question recently. So I'm sure it will come up again, and I'll be able to give a better answer next time.

I mean you referenced a couple, where single cytokines have shown efficacy in indications that are mediated by IRAK4. I guess, is there any that kind of pop out that...

Yes, I'm a big believer in IRAK4 in respiratory diseases. I think both asthma and COPD are great opportunities. I think GI inflammation, which is an area that still requires the right oral, is another opportunity. I think traditional rheumatology also makes sense. I mean lupus makes a lot of sense in terms of pathway biology. Obviously, [ RA ] has had some degree of validation, even with the small molecule inhibitor. So I mean, those are areas that I'm personally very interested in. Many of those are areas that Sanofi has expressed interest, too. So hopefully, soon enough, we'll be able to see some work in those areas as well.

What do you see as potential like theoretical safety concerns with degrading IRAK4 or anything specific with the molecule?

I don't see, personally, any specific areas of concerns. We know that adults that lack IRAK4 are pretty healthy, they've competent immune system. In our own safety data, up to Phase I, that I can speak to, we've seen good safety. So I think we're feeling pretty bullish about this program.