Good afternoon, everyone. Thank you for staying with us, and thank you for joining Kymera Therapeutics' London Healthcare Conference. My name is Kelly Shi , one of the biotech senior analysts here. In this fireside chat session, we are very pleased to have Mr. Nello Mainolfi, Chief Executive Officer, and also Mr. Bruce Jacobs, Chief Financial Officer, for this session. Welcome both. Maybe before we dive into individual programs, could you actually discuss Kymera's technology platform? How is it differentiated from other protein degrader technologies? And also, what have been the key learnings since you founded the companies?
Thanks for the invite. Let's see how this might work, so thanks for having me in London. I actually did. I started my PhD almost across the street from here, like 20 + years ago, so it's good to be back, so Kymera, so we founded Kymera with the vision of really building a new generation of medicines, so we've always been a medicine-focused company using protein degradation to go after targets that have not been drugged before or not drugged fully, and so what that meant is actually focusing on two key problems that we wanted to solve. One was, which I think has been extremely unique at Kymera, is how do we select the best target for the technology? And then the second problem has been how do we build the capabilities to do things that have never been done before?
I believe these two aspects differentiate. These are two main aspects that differentiate Kymera in not only the protein degradation space, I would say in the biotech space in general. For target selection, we had, now eight, nine years ago, taken as an assumption that targeted protein degradation as a drug modality had been proven both clinically and commercially by drugs that work by this mechanism. For us, it was not really about we need to have a platform proof of concept, but for us, it was about how do we build the most innovative medicines possible? We used, I would say, four key pillars that have been and never have changed, not meaningfully, have been driving our target selection strategy. One is going after proteins that have not been drugged or drugged fully, where protein degradation is actually solving a technical problem.
It's not because we can degrade the protein. Actually, we need to want to degrade that protein. The second part has been working with these, let's say, novel or not fully explored targets, working in pathways that have been validated, so we're going to be balancing the risk of a new technology and, in some cases, new targets by having clinical validation of the pathway. That clinical validation can be an upstream node that has been drugged. Ideally, we'd like to combine the clinical validation with human genetics validation for the target we want to work in. There is human genetics for all of our key targets. Actually, the three immunology programs that now are core and center of our strategy, all three have human genetics data to support their roles in the area that we're working in or to support the safety of it.
Undrugged targets where protein degradation is the way to unlock that value in pathways that have been validated, an ability to show superiority in early clinical development, so not need to wait for a phase III data to know that you have an innovative drug in diseases and in patient population that can be vast and can be worldwide, addressing hundreds of thousands, if not millions of patients with our drugs. I believe this key concept has been driving our target selection strategy from day one, and I believe it's been a concept that has really put us in a different light versus, I would say, the biotech industry in general.
And then the second part, which has taken time, has taken time and money, and actually the most important capital, which is the human capital, to get to the place where we are today, which is building world-class capabilities. We've shown, and only you've seen a new meaning. The public has seen part of it, our ability to go after targets that have not been drugged before, transcription factors with highly specific chemistry, whether it's STAT3, STAT6, or others that you'll see maybe starting from next year. We now have built capabilities that allow us to identify binders to proteins that have been not drugged or not bound to in the past. So I've talked about these two pillars.
I would say maybe the third one, which is our ability to translate our programs into the clinic, has been, I think, I would say at the beginning unexpected and now feels like it's one of the key signatures of Kymera, which means that the profiles that we've developed preclinically have translated exactly almost in the clinic. And what I mean by that is our ability to degrade the target to levels that we wanted to, our ability to have the right PK, the right availability in tissues that we needed to, our ability to see the safety that we had seen preclinically, and more importantly, our ability to translate the efficacy, at least so far, the early efficacy into the clinic. So we've put five programs in the clinic with the most recent STAT6.
Maybe aside from STAT6, that is very early still. In all the programs, we've seen a really almost impeccable translation in the clinic.
Fantastic.
Maybe I'll pause here. In my answer, I think it was good. I incorporated both the differentiation and what we've learned along the way.
Yeah, well done. Thank you for sharing great learnings. So at the first beginning, when the PROTAC technology, another high-level question, when the PROTAC technology actually emerged, what attracted the investor community is based on the biology mechanism of action. PROTAC actually can target un druggable targets. And Kymera is pioneering and also excels in terms of finding the suitable targets across both oncology and I&I and be able to make actual excellent PROTAC molecules. So over time from these internal learnings, do you have a stronger belief that PROTAC could actually scale up when we see more capital invested into this space? And also in terms of target selection, compare un druggable targets or with established clinical data like small molecule drugs, PROTAC be able to make it better?
Yeah, so a few questions in there. So let's start with maybe one way to answer your question. I think 10 years from today, we will look back at the mid-2020s as the years in which targeted protein degradation started to show the real potential. And 10 years from today, I think we'll look back and say that targeted protein degradation is a necessary tool in the toolbox of every biopharma companies to address key diseases and key biologies. And I think it will be one of the most successful modalities that we've ever developed in drug development for the simple reason that if you look at what the technology is able to do is combine the power of knockdown, genetic-like knockdown, for example, with the flexibility of small molecule, oral small molecules. So really the sky's the limit.
And I feel like the limitation in the space has been driven by both our imagination and our ability to be bold with target selection. And again, going after targets that are actually addressing underlying well-understood biology versus going after targets that we know we can degrade. But the field is moving, and I'm so psyched that many other companies outside of Kymera are embracing the opportunities and challenges. And you can point to multiple programs outside of our pipeline that I think really are going to the root of what this technology can do for patients. So I think the best is obviously all in front of us.
Terrific. Besides oncology and I&I, what other therapeutic areas do you think could be attractive for PROTAC companies?
Yeah, I mean, there is no relationship between targeted protein degradation and a disease area. There is no correlation of success rates. This is truly a disease-agnostic platform technology. We have done, I think, a really good job demonstrating that across both oncology and immunology. As you know, we are now focusing, at least in clinical development, solely in the immunology space. You'll see novel programs that will continue to address key undrugged and key untapped opportunities in immunology with potential to impact millions of patients around the world. But I think it's our responsibility as the space to test the power of this technology beyond these early disease areas. As you know, Arvinas is doing exploring neuroscience. We internally have early programs in other areas beyond immunology.
I think if I fast forward Kymera 10 years from today, I expect that there will be developing degraders in a multitude of other disease areas.
Terrific. Maybe let's dive into individual pipeline program. Given that the STAT6 data is actually imminent, maybe could you walk us through key findings from the preclinical studies? What gives you confidence that these results could translate effectively into clinical outcome?
Yeah, so as you know, when we've started to talk about degraders, our degraders in immunology, the key value proposition, I think the key insight that we saw, I probably would say before others, but is that thanks to the catalytic power of the technology and I think our ability to identify the right targets, we can bring forth a new concept, a concept that has actually never been reproduced or produced before in clinical development, which is having small molecules, oral small molecules that have the clinical efficacy profile of an injectable biologics. And there is no better target than STAT6 to really elucidate this concept. So we have a pathway that has been well validated by upstream biologics, IL-4/ IL-13. So we have an IL-4 receptor alpha, like dupilumab. We have IL-13 biologics.
These drugs have shown that you can block IL-4 /IL- 13 signaling and have amazing impact in a wide variety of Th2 diseases. I would say that potentially can change lives of millions of patients. STAT6 is a very unique target because it's the selective transcription factor for IL-4 receptor alpha. When IL-4 receptor alpha is activated by the ligand, STAT6 is recruited to the receptor. We actually have crystal structure of these interactions. We're able now to go with our highly specific degrader and remove STAT6 from the cell and block the pathway at the receptor level. We're basically one step removed from IL-4 receptor alpha biologics like dupilumab. What we've shown preclinically is first that we have an exceptionally potent degrader. It's a picomolar. At picomolar concentration, we can block IL-4/IL-13 in human cells.
We can show in a variety of preclinical species that at low daily oral doses, we can remove STAT6 from blood and skin of a plethora of, again, species from non-human primate to rodents. More importantly, when we use either mechanistic or efficacy model of Th2 inflammation, like an asthma model, we're able to block not only downstream Th2 biomarker, but also readouts of disease impact, at least as well as dupilumab does in those models. We've also seen really good safety. We've seen no adverse events in any of our preclinical species. So, showing us that so far, degrading STAT6 can be done effectively and fully with an oral degrader, and degradation of STAT6 is well tolerated.
So so far, we have an amazing opportunity to draw the line between one of the most robust preclinical packages that I've seen and the beautiful blueprint that Regeneron and Sanofi have built on how to develop a Th2 drug that we can learn from and develop maybe even more effectively or efficiently an oral degrader that has a really different goal here. Our goal is not only to help the 1 million patients that are on DUPIXENT today, but it's really to address the other 149 million or more patients around the world that have Th2 inflammation that right now do not have access to an advanced therapy.
Super helpful. And for the phase I data readout in healthy volunteers, could you point to us what are the key biomarkers we should look at?
Great question. We've shown preclinically that if you block STAT6, if you degrade STAT6, you block IL-4 receptor signaling. And we've shown that that's true in a variety of contexts, many of which we've published, many of which you will see in the next few months. Again, I'm talking about preclinical data. What we know is that, and what the biology tells us, if you degrade effectively STAT6, you will phenocopy, based on the data we've shown preclinically, IL-4 receptor and IL-4 / IL-13 signaling. We believe the key data from the phase I study, the healthy volunteer phase I, which we will have in the first half of 2025, will be that we can degrade STAT6 robustly in blood and skin, and that degradation is well tolerated.
That is the key de-risking event because we know that by degrading STAT6, we block the pathway. And so from there, we can actually draw the line into disease impact. As some of you know, or many of you know, other drugs in the space, including dupilumab, have shown that you can modulate some Th2 biomarkers also in healthy volunteers. I would say that there is no established correlation between reduction of, let's say, TARC in healthy with disease impact because healthy volunteers are not the patient population. The levels of TARC and, for example, IgE is very low in healthy. So I would say you can show that you can reduce the slightly measurable levels of these biomarkers, but I don't believe that is a way to quantify the activity of the drug. It is, I would say, more of a yes or no question.
Do we also impact these slightly measurable Th2 biomarkers? And obviously, we'll look at them and we'll disclose them. If you look at the dupilumab data, it's anywhere between 20% and 40%. So if you go into patients, it's a whole different story. Those biomarkers and many more are elevated. We know the dupilumab blocks them 80% or more. And we know that actually when you block those, you will see also impact on clinical endpoints. And so doing that experiment in patients that we will do after the healthy volunteer would be really where biomarkers are critical. Going back to healthy volunteers, degradation, safety, PK is really the key data point for this study.
Fantastic. So when we have this phase I healthy volunteer data, if you check all the boxes, biomarker and also safety and the initial efficacy, how indicative it is for the patient trial success? Are there any other previous trials actually we can actually leverage, I mean, including also biomarker data we can leverage to make a proxy?
Yeah, as I said, what others have shown, if you block IL-4/IL-13 signaling robustly, you have efficacy in at least eight different diseases going from AD to asthma to COPD to prurigo nodularis to EoE, and I'm not going to mention all of them. And you can have a drug like DUPIXENT that is a $15 billion drug. Next year will be $20 billion drugs in a few years. I would argue a small molecule can definitely expand patient access beyond these early numbers of 15% penetration with biologics today. So I think that the key transferable data is the ability to block the pathway. So that's why I keep going to, if you show that you can degrade STAT6 well and that's well tolerated, we know that that means that we're blocking the signaling well.
That should make us all feel confident that as we go into patients, we should be seeing clinical effects.
Fantastic. We actually can find STAT6 siRNA programs actually ongoing and based in the U.K., but we have very limited knowledge data on that. Can you actually compare and contrast the different approaches targeting STAT6?
I mean, I don't think so. You have an oral drug that degrades STAT6 in the whole body. I think the STAT6 siRNA has, I'm guessing, limited applicability. I'm not sure exactly what the diseases that they would be pursuing for a cell targeting mechanism. So I think the solution is to have a drug that degrades and addresses STAT6 in all the relevant cell types. These are not only immune cells. They're neuronal cells that we've shown in the recent publications in tissue cells in the lungs, in the bronchi. So I think that we're talking about totally two different things, and I don't think we can compare the two.
Terrific. Maybe moving to IRAK4, that's actually the most advanced program at Kymera in immunology. So recently, Sanofi made a decision to expand the current phase II trials to phase IIb. Can you first help us to understand the timeline and what is the reason behind this modification?
Yeah, so the initial studies that started actually roughly a year ago were designed. Let's use the HS study that, again, was started roughly a year ago. That was designed with one drug group and one placebo group, and usually, that study design is defined as a proof of concept study. If you have ambitions to go into phase III, wisdom as well as regulatory agencies will ask you to do some dose range finding, and so the question that we and Sanofi asked is, how do we explore opportunities to accelerate development of this drug, given that obviously time is precious for everybody, patients first? And then what can we learn early from these studies in order to support a further investment and expansion, so there was an interim analysis that was done early this year by Sanofi that was focused on safety and efficacy.
With the data from that interim analysis, there was obviously confidence to continue to invest and invest further. And so the decision was made to, instead of doing a proof of concept, then a phase II b, then a phase III, was to say, let's use this phase II study and design it into a seamless IIa , IIb study. And that obviously increases or extends the timeline to phase II data but shrinks the overall timeline quite materially, which was the initial goal. And so instead of having now the phase IIa proof of concept data in the first half of 2025, we will have phase IIb , so multi-dose, dose ranging phase IIb data in 2026.
Based on IRAK4 biology and maybe focus on HS, which is known now actually has a substantial market opportunity, how do you think IRAK4 actually fitting the landscape next to maybe like IL-17 agents? And in terms of the targeted patient, would that be differentiated or in terms of severity? I mean, what is the trial design and angle to bring IRAK4 into this landscape?
So our TPP for IRAK4 and folks at Sanofi, including Paul Hudson, has actually mentioned this. So hopefully, I can repeat those concepts. The TPP for IRAK4 degrader in HS is developing a drug with good efficacy and a good safety profile that we believe will be highly competitive in a market that is dominated by biologics. When I say good efficacy, my interpretation of that concept is we don't have to be competitive with the best in class efficacy, like let's say, let's assume the IL-17R.
But because I think what we can combine is the ability of this pathway to be pleiotropic to help many signs and symptoms of HS and be the only, hopefully, by then, the only approved oral drug that has both strong efficacy and a safety profile that doesn't require laboratory testing or doesn't hold a black box warning, which other drugs, especially in the JAKs family, would have.
Lastly, maybe quickly because we're running out of time for TYK2 program, what is your vision on the TYK2 degrader actually can bring additional benefits compared to other TYK2 targeting agents?
Yeah, I love TYK2 program because it's the most underestimated program in our pipeline, and I love these stories. So the reality is that TYK2 is one of the most well-validated targeted immunology. In terms of human genetics, there is rarely a better target than that. We have learned in 20 years of doing small molecule drug development. I've been part of that in my previous company, small molecule drug development in immunology. Small molecules occupancy-based technologies cannot reach the level of pathway inhibition that biologics can. In addition, TYK2 has a scaffolding function that is not addressed fully by small molecule inhibitors. So we have two advantages. One, we can reach full pathway engagement by degrading the target catalytically, like we've done with all of our programs already and we know we can do.
So we can block the pathway fully with 95% + degradation, and we remove the protein and address the scaffolding function. Our goal with TYK2 is not to have just another TYK2. I think we have plenty of those. It's to have a molecule that can mirror, can compete with the biologics in the space. And by that, I mean the IL-23 biologics. And I believe we will be the only asset that has that potential. Now we've seen that even other small molecule agents in the same pathway are not quite able to get there. And I think our TYK2 can, but data will be king. So we'll see.
I lied. One last quick question. So in 2025, do we expect the new targets announced by Kymera?
I hope I will not regret saying this, but yes, 99% of the probability we will share a new target in immunology in 2025.
Fantastic. Thank you for a very insightful discussion. Thanks to everyone for attending.
Thank you.