Hi, good morning. I'm Eric Joseph, Senior Biotech Analyst with JPMorgan. Our next presenting company is Kymera Therapeutics. Presenting on behalf of the company is CEO Nello Mainolfi. There will be a Q&A after the presentation. There'll be mics going around the room, and for those tuning in via on the webcast online, feel free to submit a question via the digital conference book. With that, Nello.
Thanks, Eric. Thanks everybody for joining us today. Thanks for the invite, Eric, and the opportunity to present the story here. Let's start here. To provide a bit of context, Kymera was founded in 2016 with the goal and mission actually to building a fully integrated biotech using targeted protein degradation to develop a new generation of medicines. Just for those that are not familiar with the technology, I will spend, you know, 10 seconds. Targeted protein degradation is the technology that allows you to degrade, remove, eliminate, ideally disease-causing protein from the cellular localization with a small molecule-based modality. It really combines the power of genomics medicine with the flexibility of small molecules.
Huge potentials, and it's actually our responsibility, not just the opportunity that we have to build a company that can deliver transformative drugs using protein degradation. We are focused, at least internally, on oncology and immunology, although the technology is clearly disease, protein type, tissue type, organ type agnostic. Any company in this space will have opportunities to expand beyond these indications, as we will with time. We on our track to becoming a global commercial stage company, I would say we're still early towards that end goal. In the past few years, we've accomplished quite a few things of note. And maybe I just wanna highlight a few for you all today. We have now four clinical stage programs. Actually, one going into phase II soon and three in phase I.
We have a discovery engine that allows us to deliver at least one new molecular entity into the clinic per year. We have demonstrated for the first time that degraders can be used safely and effectively also outside of oncology in complex diseases like HS and AD. Our data that we shared in December demonstrated for the first time, although early, that you can degrade a protein and deliver not only a biological, but also a clinical differentiated and superior outcome than small molecule inhibitors. I'm referring to KT-474 and IRAK4 degrader data that we'll go into in a few minutes. Something that we're very proud of that now we've had three different drugs in three actually different contexts. I would say actually four different contexts.
In healthy volunteers, in patients with immune diseases, in patients with liquid tumors, in patients with solid tumors, we've seen fidelity of translation of PK, PD, and safety. I think we're proud to say that we're the first company that was able to show and demonstrate that our molecular design and how we plan our studies continue to show fidelity of translation. We are focused, as you'll see in a minute, on deploying the technology against targets where targeted protein degradation is really the only way to elucidate that biology or clinical outcome or the best way to do it. Our programs will be either first in class, a novel kind of target within validated pathways or best in class approaches. We're well-capitalized.
We have about $560 million as of the end of 2022. As we said today in a press release, that will get us into the second half of 2025. More importantly, that cash will allow us to get through clinical proof of concept of KT-474 in a randomized phase two study, and also through early proof of concept of our oncology pipeline. Our IRAKIMiD program 413, our STAT3 program three three three , as well as our MDM2 program 253. Lots of opportunity to generate value in the next few quarters.
I've actually touched on most of what you see on these slides. Maybe highlighting a few things that we believe make Kymera unique, not only in the small companies, but I would say in the whole protein degradation space, including large and small companies. I mentioned target selection. We go after undrugged or poorly drugged targets where protein degradation is the only or best way to do it. Our platform is continue to deliver really cutting-edge science in the space. We've talked about E3 ligase expression, differential expression driving different pharmacology. This is something that we continue to invest in, hopefully we'll be able to share more.
We have announced in the R&D Day on December 20, 2021, that we've started to invest heavily also in novel molecular glue approaches, only to go after targets and proteins that are not accessible with heterobifunctional degrader. Also here, we're making progress, and you'll see just an example of a program that is moving into development relatively soon. We've talked about the fidelity of translation as well as what we call first in the space. I actually will skip that, and I'll let you read that offline. On the, you know, what are the recent accomplishments, meaning for Kymera, and I would say TPD space in general, which, you know, we're one of the early, and I would say, hopefully you'll agree, a leading companies.
We've talked about the fidelity of translation in many indications in oncology and immunology. This allows us to move our, our pipeline with confidence across all of our programs. I think demonstrating that you can use TPD outside of oncology, again, safely and effectively, showing that degrading scaffolding proteins can give you best-in-class profile in complex diseases like HS and AD was a big validation of our target selection and execution, and only emboldens us to continue to use this technology in these areas of, again, complex but, you know, high risk, high reward.
Then, you know, maybe the last one to connect it to the next slide, is really how we're thinking about building on, I would still call it early success with KT-474, but to continue to propel the company into large areas of clinical and commercial opportunities in immunology heavily, as well as in oncology. I wanted to share today a bit more on the broader strategy that Kymera is taking. I think it's relatively rare for a platform company to have the first program to not only elucidate the platform well, but also show promise to potentially becoming a real drug with large commercial potential. Obviously, I'm referring to KT-474. If you actually pay attention to the data that we've shared, we have shown impact on biological pathway in IL-1 family cytokines, Th1, Th17, Th2 in innate immunity.
It's not surprising to see that we expect to expand the development program with our partner, Sanofi, beyond the derm indications that you've seen in December. There are opportunities in GI, rheumatology, obviously with RA, as well as respiratory. You know, having the opportunity to actually have that area of both development and commercialization de-risked with a partner like Sanofi that wants to be, you know, a leader in immunology, allows us to then being able to build on the success and on that financial and operational de-risking with investing in other programs, other pathways, where we can synergize the capabilities that we're gonna build along the way, again, with KT-474.
We're not gonna disclose many targets today, but I just wanted to share the pathways or at least the franchises that we're gonna be investing in. We have a program that probably has more small molecule validation than IRAK4, but also there a scaffolding opportunity that we, with our technology, can eliminate. This is another potentially large opportunity in derm GI rheumatology. You know, the back of 474, and I would say maybe more on the back of DUPIXENT antibody, we have found a transcription factor within that pathway that we can degrade very effectively, and this is another large franchise following actually the path that DUPIXENT has taken, although in this case with an oral degrader molecule.
Obviously, we've talked about STAT3 in the past and the opportunities in many of these indications. Here I'll just mention that we've been able to identify novel integrin interaction and novel molecular glue in immunology, in indications of interest, as you see there, with against a target that really has never been drugged before. In oncology, you're familiar with the pipeline. IRAKIMiD is really the first targeted therapy in lymphoma, hopefully. You were aware of STAT3 opportunities in T-cell lymphoma leukemias and potentially in solid tumors. With MDM2, we haven't shared a lot about the clinical development plans, but clearly, this is gonna be a both liquid and solid tumor opportunity.
Again, on the same theme of scaffolding complexes, we believe we have probably the best approach to go after this particular node in solid tumor. Large opportunity. Going to the next slide, just to keep the theme of the type of targets that we're going after, you can see building on success of IRAK4 scaffolding proteins. You see we have roughly five programs within oncology and immunology that we can build at the back of that demonstration of success. The other area that we're very invested in is transcription factors. Again, these are both categories of programs that only a degrader can really be successful in. Here you see opportunities in both oncology and immunology. This is a snapshot of our pipeline. The top part is a pipeline that hopefully many of you know well.
I won't spend too much time on this. We have 474 moving into phase 2 with Sanofi, and 413, 333 hopefully will be able to share impact on patients or clinical activity this year. With 253, initiate phase 1 and also demonstrate proof of mechanism. You see below the programs that I've talked to you about. I'm not gonna go into the details, but rest assured that in those four, five programs, we expect to have DCs and INDs in the next couple of years. I've told you high-level objectives. You know, we've talked about 474, the oncology programs, the novel programs that we wanna advance as well as our platform investment.
I thought in the next, maybe beyond the 8 minutes remaining, I'll take a few more minutes, just tell you about just highlights of the programs and maybe an opportunity to add some commentary from our most recent disclosure. IRAK4 doesn't need a lot of introduction. It's a key node in a pathway that has had extensive validation, mostly through upstream targeting of cytokines, receptors, and more recently with a small molecule kinase inhibitor, so blocker of the kinase function. We know that IRAK4 has a dual function of both scaffolding and kinase, and we've demonstrated for the first time that by removing the protein, you can address both the scaffolding and kinase function, demonstrating superior biology and also early clinical outcomes. The commercial opportunities are vast in both Th1, Th17, and Th2 diseases.
The most relevant data set that I think we should all take from the presentation in December was that we demonstrated that these pathways activated in both Th1 and Th17 disease like HS, and Th2 disease, like AD. That is the first time that that type of validation is being accomplished. We've run an extensive phase I study. I personally don't remember another extensive phase I study like this. We've done it for many reasons, but, you know, this is obviously a novel modality where there is a lot to learn in how you translate the preclinical understanding into the clinic. We've dosed more than 100 subjects, probably more than 120. I don't remember the exact numbers. 150, Jared is telling me from the front row there.
Clearly, this drug has been dosed to a large number of subjects, both healthy volunteer and patients, and we've shown at really high level quickly, a really strong degradation in blood and skin, in healthy volunteers impact on ex vivo cytokines and good safety. We went into the HS and AD study with the goal of really demonstrating a fidelity of translation from healthy volunteers to patients. Can we degrade the target as well? Can we impact cytokines as well? Is the safety in line, and can we gather any early signs of a clinical activity, as measured by clinical scores or symptoms? And obviously, what we delivered went well beyond our expectations. We demonstrated degradation in both blood and skin.
We demonstrated a good safety profile with even an improved safety profile with regards to the mild subclinical QT effect. We had some really promising clinical activity. I think the scores in both HS and AD, the impact on symptoms, both pain and pruritus, for just a 28-day study was, in our mind and in our partner minds, quite impressive. I won't spend too much time going through the data. This presentation actually is also on our website, and you can actually listen to our presentation in December. This slide just to show that the PK and PD was consistent with our expectations.
I would focus on the plot on the right of this slide. This shows that we were able to impact inflammation in the circulating cytokines and acute phase reactants in both HS and AD. The reason why, to me, this is the most important data is because if IRAK4 pathway was not activated in HS and in AD, degradation of IRAK4 would lead to no impact on these biomarkers. That's the most relevant piece of information from this study in my mind, the impact on these inflammatory biomarkers in patients in both HS and AD. In both blood, here you see in skin, we have impact, as I mentioned, IL-1 family cytokines, Th1, Th17, Th2, innate immunity in the skin of patients with magnitude that go beyond 90%.
Again, showing that this pathway is activated not only in blood but also in the skin of both HS and AD patients. The take-home from the clinical data is really as follows. The most impressive data in our mind was that the kinetics of response in both, in this case, EASi scores and pruritus, follows the kinetics of degradation of the target in blood and skin. We have rapid degradation for 28 days, and upon cessation of dosing at day 28, we actually are able to maintain, although reduce degradation for another two weeks. In fact, at day 42, we still retain roughly 50% degradation. If you look at these charts, you see exactly that playing out where you see maximal degradation roughly at day 28 when you stop dosing and you have cumulative effect.
You actually are able to maintain, in some cases even improve, the outcome because the pharmacology continues to play out in the next two days, in the next two weeks. I won't get into comparing numbers, but obviously in a small study, in a short study, these are quite impressive numbers, in both scores as well as, or maybe even more impressively, I would say, in the symptoms. In both AD, as you've seen in the previous slide, and in this case in HS.
Just a summary of what we've seen, we were able to demonstrate that a degrader of IRAK4 is well-tolerated, is impacting inflammation in HS and AD, is degrading the target well in blood and skin, and that impact on inflammation results in clinically relevant measurable outcomes in diseases of complex etiology like HS and AD. This type of data is really making us feel, as I said today, excited and confident that this drug could have broad impact, not only in HS and AD, but beyond these diseases in phase 2 and beyond. I thought I'd give in the next five minutes just quick highlights of also our oncology pipeline.
IRAKIMiD, which is now in dose escalation, is a program that we've designed to target a specific population in diffuse large B-cell lymphoma, called MYD88 mutant subpopulation. The reason why we devised degradation of IRAK4 as well as IKAROS and Aiolos, that's why we call it IRAKIMiD, is because we found that these two pathways are in a way complementary to each other. There is almost a compensatory mechanism that if we eliminate both, we can have really profound single agent activity. What we've seen pre-clinically that degradation of IKAROS and Aiolos around 90% and IRAK4 around 60%-70% leads to the type of activity that you see on the left of your slide here in blue, basically single agent complete remissions.
Where we are in the clinic, obviously, where we were in the clinic, this is a data set from December we're not gonna update today, that even in only in the first two dose cohorts, we're able to already demonstrate full degradation of IKAROS and Aiolos, and already about 40% degradation of IRAK4. More importantly, in these two dosing cohorts, where we're maximizing both the depth of degradation of IKAROS and Aiolos, and also the need of the extent of degradation of IKAROS and Aiolos, we actually did not see any neutropenia, which is obviously one of the key safety potential that IMiDs obviously elicit in humans.
This bodes well for, you know, as we continue to dose escalate and expect to see clinical activity as we're reaching the right level of degradation of also IRAK4, which we expect it to be at the current cohort going forward. As I said early, we expect being able to share the impact of this degradation profile in the right patient population, so antitumor responses hopefully this year. For STAT3, in a way, it's similar opportunity in terms of going in indications where there is high sensitivity to this mechanism. We divided them in two main categories. T-cell lymphoma leukemias, where we know are dependent on the level of actually phospho STAT3. Elimination of STAT3 will have single agent activity, and then potentials in combination with solid tumors.
This program is in dose escalation. What we shared in December was that even with a first cohort, we were able to reach meaningful levels of degradation. As you see pre-clinically, in this program, obviously, this is going after single targets STAT3, we need to see 90% degradation for about 24-48 hours to lead to this profound apoptotic response and to see single agent activity. As I mentioned, our first cohort, as a mean, we're already seeing close to 70%. We already had a patient that we're able to see up to 86% degradation with a very pristine safety profile. Obviously, we're not there yet in terms of the degradation profile that we need to see clinical activity, we believe we're going to be close.
Seeing also an encouraging safety profile is critical. Also for this program, we expect to share data with regards to the impact of degradation on the tumor burden of patients in 2023. Just lastly, on MDM2, this is a program. Again, our fourth clinical program, we had an IND cleared at the end of last year. This is a program that we're very excited about because for the first time, following again what we've done with IRAK4, small molecule inhibitors is insufficient to lead to a full biological effect. For MDM2, it's the same, although obviously different biology. We have tried to follow the cancer genetics for this program for 10, 15 years. We know that if you delete MDM2 in P53 wild type tumors, you see a profound antitumor effect.
We assumed that inhibition of MDM2 would replicate cancer genetics. In reality, that is actually hardly ever the case. Now we have an opportunity with a degrader to replicate the cancer genetics data. We can delete with a small molecule MDM2 and hopefully lead to this profound antitumor effect. The reason why deletion is superior biologically than or I should say degradation is superior than, I don't wanna come up with another definition now. Degradation of MDM2 is superior to small molecule inhibitor, is because in the inhibition of the MDM2-P53 interface leads to an upregulation of MDM2 proteins, the so-called feedback loop. We can overcome that with a degrader because we completely eliminate the protein.
Instead of having cell cycle arrest type of phenotype that small molecules have that require continuous dosing, we actually have apoptotic response in cancer cells that will only require infrequent dosing. That's really the rationale of the program. We see much more potency than other small molecule inhibitors in both upregulating P53 and killing cancer cells. We see profound activity in preclinical models. This is an AML model that is driven by upregulation of these apoptotic biomarkers that you see on the right of your slide. We are very interested about AML as one of the indications, not the only one, and especially venetoclax-resistant AML, which is really the main opportunities here.
You see both a single agent and in combination, we're able to solve for at least pre-clinically so far for this really high unmet need. Our development strategy is focused on phase one will be both in liquid and solid tumors. We're gonna start dosing soon in Q1, hopefully. Will be based on all the preclinical work that we've done that allowed us to identify indications where there is this high sensitivity and this apoptotic response in both liquid and solid tumor. Right now we're talking about AML and other heme indications. Next year, we'll be disclosing some of our solid tumor focus. Also here, we expect to share proof of mechanism data, so type of data like we've shared for the other programs in December. I just wanna conclude, I'm sorry if I took a bit longer.
I just wanna conclude that hopefully what we shared with you today. To be honest, what we shared with everybody in the past few years is able to elucidate to you that Kymera has done a great job identifying the right way to develop this technology. The right target to apply this technology against, and then execute against these programs in a way that was on time and with the right type of data that supports continued development. We're excited about our clinical pipeline. We're also excited about some of the other programs that we gave you maybe a tease around that you've seen before. We're well-capitalized. We have a committed team that wants to make this company a large commercial stage company and excited to engage with all of you to continue this journey.
I'll pause here and thank everybody and happy to take questions.
Great. Thanks. Thanks, Nello. Maybe I'll start out while the mics get circulated. You have the potential to go or KT-474 has the potential to go pretty broad and also deep within I&I. I guess in thinking about the phase two program that Sanofi is gonna be leading, do you have a sense of sort of where in the treatment algorithm and the severity of patients with either HS or AD they'll be looking to further evaluate 474 initially?
Yeah. No, that's a great question, Eric. What we've tried to focus in our phase 1, and again, our phase 1 was designed to really confirm PK, PD, and safety. As I've said for months, I thought I'd repeat today. We also focused on mostly, at least we try to, focused on moderate to severe patients because that's really where we believe the most unmet needs are. We haven't. We are not in the position to sharing the information that you're asking, but I would be surprised if that wasn't that didn't continue to be at least a key focus of the further development. I mean, as we were discussing yesterday, you know, these are complex diseases where the patient experience is very, very critical.
Understanding how we're improving not only lesion, but also the patient experience, the symptoms, and how they live with the disease is a critical aspect of how we're gonna develop this drug and how we're gonna engage also regulators on the development of this drug.
I guess just generally speaking, how should we be thinking about the cadence of updates with KT-474 now that its development is really in Sanofi's hands?
I would say I wanna continue to recognize Sanofi's approach to this partnership. They've been, you know, extremely close when we were leading discovery and development, and they are very engaged with us even when now they're leading the program. We have an opportunity to discuss influence and refine plans and timing. I would expect that the while obviously the communication of the data will be, you know, slightly different than what we've done in the past, I continue to expect that we'll be able to update as meaningful milestones are reached. You know, this is not gonna disappear from our conversations.
In terms of timing, we're refining with Sanofi. I would say, you know, the next disclosure will be initiation of phase II study, and, you know, eventually will be also potentially how we're thinking about the further expansions into other indications, but that's something that we're not ready to discuss today.
With some of the other, targets that you're pursuing thus far not disclosed within immunology, I guess strategically, ultimately, how are you thinking about, sort of advancing those? I guess would you seek, partnerships and at what time?
Yeah.
Would be appropriate?
I mean, it's a great question. You know, I think the partnership with Sanofi was something that we, you know, I remember when we signed it in 2020, we debated extensively whether it was the right thing at the right time. I actually don't like looking back too much, but I think, you know, given where we are today, the opportunity that this drug has, I think it's a great opportunity to have a company committed to being a leader in immunology, leading the charge with this program, and also allowing us to grow and forward integrate the company in both clinical and commercial with them.
I think with this experience, assuming success, hoping and assuming success, I think we have to be more aggressive as a company to develop on our own some of these programs all the way through the commercialization. There might be areas where, you know, there are unique synergies to be explored, but at this point, you know, we're focused on building an integrated company. The learnings from IRAK4 allow us to do hopefully a great job with the earlier pipeline as a standalone company.
The STAT3 program is interesting in that it has both applications in in oncology as well as in autoimmune indications. From fibrotic disease as well as I believe. I guess, can you just talk a little bit sort of how whether there are just different pharmacological properties needed to engage STAT3 outside of oncology and whether the target or your degrader portfolio might be amenable to an orally administered candidate?
Yeah. Starting from the pharmacology, you know, this target has really unique features as in, you can use it for blocking phospho-STAT3 presence in liquid tumors, that leads to apoptotic response. You can use it to modulate tumor microenvironment in combination with PD-1, then you can actually use it to reduce systemic and local inflammation in the right context. All of those actually can have different requirements in terms of PKPD. What we found that in immunology, while in oncology we need 90% degradation for at least the first day or so, we've seen that we can have less than that, maybe even around 50% degradation of STAT3 in immunology, that leads to really impactful anti-inflammatory effects.
Actually, in some cases, effect that is superior to upstream inhibitors like JAK1 or JAK2 inhibitors. We're gonna probably share more later in the year. We're looking at some really creative ways to think about STAT3 outside of oncology. I think right now we're not in the position to share more, but we hope to be able to share more of that as we get through the next few months in 2023.
With the MDM2 program, I guess are there particular histologies that you think might be sensitive to MDM2? Sorry.
Yeah.
More dependent on P53 or MDM2 degradation or sensitive to MDM2 degradation. Just as you kind of indicate proof of mechanism towards the end of the year, what that might that portend in terms of-
Yeah.
activity in tumors and patients?
I can always rely on Eric for insightful questions. This is a good one. The histology, it's actually I don't know how you came up with it, but it's a great question because there are some features about tumors that are very sensitive to MDM2, that are actually dependent on the type of cells that this tumor are generated from. I'm gonna leave this for, you know, another day, for a discussion for another day when we're gonna share more our translational strategy and our sensitivity strategy.
There's clearly an opportunity, and I think you can see through, you know, thinking by AML and some other solid tumors that even the small molecules have been developed, that there is a feature that is common across some of these tumors that are sensitive, where levels of P53 are gonna be critical. With regards to what we call a proof of mechanism, it's really for us, you know, as I've said in the past to many of the people in this room and hopefully outside, that for us is basically de-risking the molecule. Is the molecule doing what it's supposed to do? As you know, especially in a new modality, that is the most critical question in early development. Is the molecule degrading the target at the levels and the kinetics that you need it to do?
Is the safety following what we've seen in preclinical species? As we've done for the other two programs where, you know, with the data that we shared in December, we now feel much more confident going forward. We hope to being able to do that with MDM2 as well. Obviously, going in AML, we might be able to have even more, let's call it proof of biology data, because as you know, that disease allows you to measure many other biomarkers. For now, we're just saying, you know, proof of mechanism is what we're gonna be able to share in 2023.
I'm sorry if I missed it here in the slides. Route of administration with.
This is a once every three weeks IV. We actually designed this is can be dosed orally, but we designed the IV because we need this really initial high level of drug that leads to this rapid apoptotic response. Then we need a clearance of drug so that the normal cells can recover while the cancer cells have died or are dying.
Okay, great. I'm just gonna pause here for any questions from the room. All right. I think we'll leave it there for time. Thanks a lot, Nello
Thanks, Eric. Thanks, everybody.