Go back and forth, so all right, we should get started on time. All right. Welcome, everyone. This is the Fireside Chat with Kymera Therapeutics. My name is Vikram Purohit. I'm one of the biotech analysts with the Morgan Stanley research team. Before we get started, I need to read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please see, please reach out, excuse me, to your Morgan Stanley sales representative. With that, very happy to have with me, Nello and Jared from the Kymera team. Thank you both for joining us.
Thanks, Jared.
Yeah, thanks, Vikram.
We have a lot to talk about within your pipeline. But first, Nello, maybe just to level set for everyone, do you want to provide some opening remarks on some of the key inflection points for the business this year? And then we can go from there.
Yeah, maybe just to provide just a bit of context. So Kymera is a company that was founded with the goal of developing a new generation of medicines using protein degradation. Protein degradation is a small molecule-based modality that allows you to remove disease-causing proteins with small molecules. So it has combined the power of, let's say, genetic-like knockdown with the flexibility of small molecules. So we really have an uncharted breadth of opportunities in important diseases with limited treatment opportunities. We've decided to focus for the early part of this phase of the company on oncology and immunology in pathways, to be honest, that overlap the two spaces where we can actually synergize the capabilities as well as the drug development opportunities.
As we continue to evolve the company to eventually become a commercial stage integrated company, which is a commitment that we have to the technology, to the modality, and to patients, we obviously continue to evolve how we think about target space, opportunities, technology, evolution. We're really proud to say that while we continue to be a company focused on clinical execution, we have four programs in the clinic. We also are a company committed to innovation, evolution of our discovery pipeline as well as platform. We're probably the only company out there that, again, works in oncology and immunology, that has both heterobifunctional degrader efforts as well as molecular glue efforts. We have efforts using E3 ligases with differential expression.
So we would like to think that we continue to innovate ourselves and continue to stay relevant while we continue to execute at clinical stage programs. With regards to our pipeline, we have four, as I mentioned earlier, four clinical stage programs. We have the more advanced program that is in partnership with Sanofi that is just about to start our first phase II study in HS. There is a second phase II study in AD that will start hopefully shortly thereafter. We have three oncology programs in phase I. Two are in the advanced stages of those escalations, KT-413, an IRAKIMiD degrader, and KT-333, which is a STAT3 degrader.
We shared early phase I data in June for both programs, demonstrating, again, great translation of PK, PD, and safety with both programs, showing that we were either at or approaching degradation profiles that we expect to be clinically active. And for both of these programs, we expect to be able to share early proof of concept data, so antitumor activity in the right patient populations this year before year-end.
And then we have a fourth program, MDM2, that we started dosing only recently in Q2, where we expect and hope to share early PK, PD, and safety this year. I would also add, as we've said in meetings today, that we're planning to have an R&D Day early next year, where we will be talking about the evolution of our immunology pipeline with disclosure of one or two new programs that will enter clinical development thereafter. So maybe I'll pause here, and we can spend time on some of these programs.
Sure. Sounds good. Thank you. Let's start with I&I with KT-474. Maybe the best place to start, Nello, is the recently initiated phase II study for KT-474, which is a partnered program, obviously partnered with Sanofi. Clinical trial listing recently became available for that study, and maybe we can talk a little bit about the way that study is designed. I guess my first question is, the primary endpoint is a decrease in AN count rather than a HiSCR response. Two obviously related measures, but how did you and Sanofi think about the best choice of primary and secondary endpoints for this study?
Yeah. So, happy to answer this, and I'll let Jared maybe comment on the actual specifics. But just to reiterate, high level, the goal of our phase II study is to demonstrate clinical activity versus placebo. As you know, we had a small phase I study where we recruited both HS and AD patients. That was not placebo-controlled by design, obviously, because we had other goals, but we saw some really exciting early signs of clinical activity. So we want to confirm those hopefully, with having a study that is designed to demonstrate differentiation of the treatment arm versus placebo arm. As in a phase II study, it's really up to the sponsor to decide what are the primary endpoints versus secondary endpoints?
In reality, we will collect all the relevant endpoints and measures of disease burden that any other study in HS have collected. So, you know, what we decided to be primary versus secondary endpoint, to be honest, is some more of an academic conversation, but it's still a relevant question. Maybe, Jared, you can comment on why AN count being the measures that we decided to focus more as, let's call it, the primary endpoint.
Sure, yeah, you know, in phase one, in part C, which was in patients, you know, we spoke with various HS KOLs to decide what was the most reliable endpoint to use in that particular small study. And they recommended that we use a continuous variable to measure skin burden regions, which is the AN count. So that's why we included it in part C. And I think when Sanofi and Kymera were discussing the endpoints for phase two, it was also again felt that AN count as a continuous variable would be the most reliable and straightforward measure to help us show efficacy relative to placebo in that study. But as Nello mentioned, there are multiple secondary endpoints that include all the different sort of HiSCRs.
Of course, you need AN count to derive your HiSCRs, whether it's HiSCR 50, 75, or 100. We have other measures of disease severity, symptoms like pain, quality of life, et cetera. So it's, it's pretty fully loaded in terms of all the relevant HS clinical endpoints that we have in phase II. As Nello mentioned, whether, you know, AN count is primary or secondary isn't relevant. Ultimately, you know, down the road when it comes to deciding if this program moves to phase III, what would be the appropriate registration endpoint? That will, of course, require a discussion with FDA at that time.
Understood. Okay, great. And then on safety, the trial listing notes an exclusion criteria for patients with Long QT syndrome, patients with certain CV issues, excuse me. Is this just kind of a general safety measure, or is it related to something that you observed in your phase one study for KT-474?
Yeah. Maybe just to provide also here a bit of context, just reminding everybody that in the healthy volunteer study, the MAD portion of our phase I, we uncovered these subclinical non-dose response and not concentration responses QT prolongation, where the median within each cohort was between 10 and 20 milliseconds. Actually, when we ran our phase I part C study, which was in patients, it was from two weeks, became a four week study.
We actually uncovered that these, again, subclinical signal that we saw actually appearing and plateauing at day seven, now that we could see beyond day 14, was actually resolving spontaneously as we continued dosing through day four through day 28. So in the part C, we actually show that this QT finding that again, was subclinical, never becoming an adverse event, would resolve on its own as we continue to dose. So that's the context maybe behind your question.
Okay.
With regards to your question, I think the only relevant part, the rest is standard for phase II study, is with regards to patients that have prolonged QT as a genetic feature. This is a tiny part of the population, and given that we're still in the process of refining and characterizing this phenomenon, we wanna make sure that we avoid recruiting patients that have a long QT as a predisposition already.
Sure. Okay, understood. Can we talk about the profile of patients being enrolled? What have they previously been administered? What are they allowed to take while they're in this trial, et cetera?
Yep. So we'll be enrolling moderate to severe patients with HS. You know, we've specified, you know, some of the parameters that will help to sort of define the moderate to severe in terms of minimum number of AN count and maximum number of draining fistulas and even a minimum CRP. Those are fairly standard. We want patients who are mostly naive in terms of prior systemic therapies. So no prior biologic therapies, except for about up to 20% of patients can have had a prior biologic therapy, but they must have come off for a lack of tolerance, not due to disease progression. So the majority of the patients who will be on study will be naive to prior biologic therapy.
Okay.
The goal there is, again, designing the study to evaluate clinical activity. We wanna give, obviously, the drug the best chance to demonstrate that.
Sure. Understood. Okay, just building on that question then, or building on that point, rather. Assuming the study works out the way you and Sanofi hope for it to work out, and there's a clear signal, what would you expect the pivotal program to look like? And then eventually, looking a couple of years forward, where do you hope that 474 sits kind of within the HS treatment paradigm between, you know, antibiotics, Humira, maybe other biologics that may be on the market?
Yeah, I mean, you know, unfortunately, there's only so much we can share given that, you know, Sanofi is the actual sponsor of the study, and we're not in the position to comment, you know, what is the late development plan for this drug. But I think what, what we can say, hopefully, safely here, is that, you know, the value proposition, we believe, for an IRAK4 degrader like KT-474, is to provide patients with a- an active, well-tolerated, and convenient oral option that we believe will have a great opportunity to impact their quality of life.
I don't think we are here trying to demonstrate or to design studies to demonstrate necessarily how we're competitive versus drug X or Y, but I think we're trying to develop a drug that would be a meaningful drug that will change how people live with this disease. More importantly, with a convenient and safe options that right now, is not provided by any other therapy, either approved or close to be approved in the landscape of HS today.
Understood. So you mentioned obviously the HS study, the trial listing is up. The study is gonna be recruiting patients soon. AD, you mentioned that that study is going to be initiating very shortly. Beyond HS and AD, you've previously talked about additional indications for 474, and my question there is, is evaluation of 474 in those additional I&I indications, is this more of a business/pipeline prioritization decision at Sanofi that needs to happen? Or, are you and Sanofi waiting for initial data from the AD and HS programs to figure out where else 474 makes sense?
Yeah, I mean, again, I can't speak for business consideration from Sanofi, which I'm sure are relevant to any pipeline decisions that they make. I would say that the way we are experiencing the collaboration is that there is obviously clear interest to maximize both the patient and value for this drug, patient impact and value for this drug. And I think it would be surprising for anyone that for anybody that understands this biology and the clinical opportunities, it would be surprising that the development program ends with HS and AD. So obviously, two things need to happen to think about expanding beyond HS and AD. One is, you know, for the two companies to align and obviously for Sanofi to be supporting other indications.
And as I said, there is plenty of both preclinical and clinical data that would support wide variety of other indications, and then obviously, more clinical experience that would continue to support developing a drug like KT-474. You know, I unfortunately can't share more, but I think we, we're both excited about the opportunities for this mechanism. And as I said earlier, I can't imagine that there are many drugs out there, if any, that have both the breadth of anti-inflammatory signature that an IRAK4 degrader has, as well as the convenience and the power of this mechanism. So I think we're both aligned that we want to maximize opportunities with this program, but it's at this point too early to tell to the audience where we are in that particular workflow.
Got it. Got it. Okay. Fair enough.
Hopefully, that meant something. I don't know if -
No, it's helpful.
I tried to avoid the question for as long as possible.
Let's stay on I&I, maybe take a step back from 474. You have a number of I&I-focused earlier stage programs in your pipeline now. I guess, what do you think, which aspects, rather, of Kymera's platform do you think make it particularly well suited to go after I&I, maybe versus other platforms that are out there?
Yeah. So, we were the first company to decide that a degrader approach would have huge potential in immunology. And in fact, you know, I remember early in the days, you know, there were questions about, you know, why we are taking a degrader into immunology. That's, you know, that's a bold approach. We've learned a ton in what it means to develop, to discover, optimize, and develop a, at least early in clinical development, a degrader in immunology. There are particular platform learnings. There are both the pharmacology, safety, development details that we've continued to learn at Kymera that have impacted how we think about our pipeline design. And I will say that as we've seen the immunology landscape evolve, I think it's clear that there are a few pathways that have been fully validated.
There are a few drugs that have, you know, multi-billion dollar markets. I think the future of immunology is all small molecules, for sure, at least from where I sit. It's about having meaningful drugs that combine efficacy, safety, and convenience for, you know, millions. We're talking about millions of patients here, right? We're not talking about 10,000 patients. And so in order to have a global drug with meaningful impact, you have to have an oral drug that is accessed by the broadest population. Now, the biggest nuance in what I've said so far is what we characterize as small molecule. Small molecule degraders is the only class that can get close to biologics-like activity because of the mechanism of action.
And so we've, we see that the evolution of our pipeline is to have oral small molecule degrader drugs that can provide meaningful benefits to patients in these large, large commercial opportunities. And so as we go into the new year, and we'll share at least hopefully a couple of these mechanisms, I think it will appear clear why a degrader platform is perfectly suited to transition heavily into an immunology landscape.
Got it. Maybe one final question on I&I then. As the non-474 programs in your I&I pipeline progress, what's your appetite for partnerships? And I think it's a question that comes up just because of the way you had established a partnership with 474 early on with Sanofi. How do you think about it now, given that the company's evolved a little bit more since then?
Yeah, a lot more, I like to think. But, yeah, so, I, I mean, you know, I think, a company like Kymera, so we, we have, again, four programs in the clinic. We're probably gonna have three or four more in the next, I don't know, 15, 18 months. I haven't done the math, particularly well at the end of this grueling day. So we, we will have a broad pipeline, many programs in large indications. So it's, it's only probably rational to expect that Kymera will continue to think about partnerships as a way to forward integrate the company. I, I think what we don't want people to assume is that we are going to partner all our immunology programs, and we're going to keep all our oncology programs.
I think, as you, as you said, we've evolved either a bit or a lot, and so, I think we understand more, now, what is it that a partnership needs to bring to the evolution of the company. And I think it's a lot about what are those win-win opportunities. I think it's fair to say that we can constantly develop programs into key inflection points, and then, depending on the market opportunities and the areas that we want to invest as an independent company, I think we need to figure out where is the right partner for that particular opportunity.
There will some that we will take all the way to registration and commercialization alone, and there'll be some that we will partner either at commercial stage or a late development stage. Then that's, I would say, the base case strategy. There will be some other partnership opportunities that might not fall into this category, but those are maybe more outside of the norm than the base case.
Got it. Okay. Maybe we should now transition to oncology. I wanted to talk about KT-413, your IRAK inhibitor degrader, and KT-333, your STAT3 degrader. Both molecules or data sets, as you mentioned, by the end of the year. Let's tackle 413 first. So, just quickly remind us what we know so far about the molecule and what you're hoping that the data set by the end of the year establishes for you.
Yeah. So what we know is that by dose level 4, which we showed in June, we were able to demonstrate in blood the levels of degradation that preclinically was really correlated with high level of antitumor effects. Now, at least as of June, we were not able to show what was the tumor degradation because we've not done mandatory tumor biopsies, so we obviously are looking for the opportunity to have tumor biopsies. So there is, I guess, that gap in knowledge about is the blood degradation mirrored in tumor. Preclinically, that was the case, so we're working under the assumption that that is the case.
So, what we hope to be able to share, again, it's an early proof of concept, at best, a handful of patients with, in this case, MYD88 mutations, where we're seeing meaningful antitumor activity. Now, what we're not gonna be able to see, just based on N's, is, you know, what we're not gonna be able to discuss is response rate as a percentage of activity versus a number.
I mean, obviously, everybody can do the math, but what I'm saying is, for us to have a reliable response rate number and even duration of response, it's probably more to do with an expansion cohort, where we'll have a large number of N's with them all at the right dose, and that's where the full clinical activity of the drug will be evaluated. But being able to say, look, the IRAKIMiD impacts the life of patients with MYD88 mutant tumors or not, is what we're trying to accomplish this year.
Understood. And then one commercial question on 413 : How large of a patient population is MYD88 in DLBCL?
I mean, it's about a quarter of diffuse large B-cell lymphoma, so it's about between 2,000 and 3,000 patients per year in the U.S. that have MYD88 mutation. That is irrespective of line of therapy, so it depending on, you know, where we obviously land as, hopefully, first approval versus upline approval. That's, you know, mechanics that will- we'll have to be elucidated as we continue to develop the drug.
Got it. Okay. And then same question for 333, I think. What do we know based on your most recent data cut this summer, data presentation this summer, rather? And then, again, what do you hope, the data by year-end helps de-risk for you?
Maybe, Jared, what's the question?
Sure. The data we presented on KT-333 was back at ICML in June. We had a poster there, and we had presented data mostly through dose level three, although we were enrolling in dose level four. At that time, we showed, you know, very nice knockdown in the blood with patients averaging as high as 85%-88% knockdown, lasting, you know, two to three days, which was close to the target that we had aligned on based on our preclinical data, where 90+% knockdown for two to three days was giving a very strong anti-tumor activity. So we noted that back in June, that sort of knockdown was accompanied by a very acceptable safety profile, with very predictable PK.
So since that time, you know, we've been continuing to enroll onto the study. We have the sites that are needed to allow us to enroll not just broadly, including solid tumors and lymphomas, but also to start to focus on the target patient population as well, which in this case, for monotherapy activity, is at various T-cell malignancies, including Cutaneous T-Cell Lymphoma, Peripheral T-Cell Lymphoma, and LGL leukemia. So we have sites that are able to allow us to bring those patients onto the study.
So what we hope for by the end of the year is to be able to present additional safety, PK, and PD data as we continue to enroll and dose escalate, but also start to be able to show, you know, a handful of patients within that target patient population, some preliminary signals of anti-tumor activity, especially for patients who are being treated at higher doses, where we're getting the desired pharmacology that should translate into anti-tumor responses.
Got it. Okay, great. We have around four minutes left. Let's just stay on oncology. 253. So proof of mechanism data for that molecule by year-end. What have you guided to there in terms of how large of a data set that could be? Again, what's your, what's your hurdle there?
I mean, maybe I'll take this one. So for MDM2, the key question for this program, as many know, is protein degradation driving a differentiated clinical response by a differential biological signature? So we're able to, at least pre-clinically, drive to an apoptotic response, and with this infrequent dosing, we're able to manage the known safety challenges with upregulating p53. So for us, it's critical, as early as possible, to show that we're hitting PD that we believe is meaningful with a good safety profile. So that we're closer to actually bridging the gap of, does that PD result into responses, and are those happening before we hit those limiting toxicity? That's really what we're trying to do.
This year will be mostly focused on, you know, again, early cohorts where, you know, we want to show again, that for the fourth program in a row, hopefully, that will be the case, that we're able to translate our preclinical profiles of PK, PD, kinetics of PD, as you know, for this infrequent dosing, they need to be really accurate, and the nadir of degradation and resolution of degradation, as well as safety. With that data in hand, we'll go into next year, where we expect to be talking about anti-tumor activity with more confidence. That's usually how we like to think about clinical development for degraders that actually are a differentiated mechanism, as we know.
Got it. Okay, great. In terms of pipeline areas of focus beyond the four that we discussed, what are other, other milestones, other developments that you think are not well followed, well appreciated by people, that deserve some more digging and deserve some more attention, especially over the next year?
Yeah, I mean, I think I would start with the fact that, you know, we're a company that has executed on all the programs that we had pre-clinically. When we IPO'd, we were in a pre-clinical program, and, you know, three years in, we have a program in phase II and 3 programs in phase I, all with supporting positive data. Maybe that's place to start. Then I would go into, maybe how we're evolving the company, in what type of targets we choose and what type of clinical and commercial opportunities we're focusing on. What type of problems we're trying to solve with our platform. I would say that if we didn't learn in the past 5 years, we would probably be doing a bad job, too. So, I think I do want to say that we have an evolved appreciation for what this technology can do.
I think as we start to disclose more programs, I think it will become apparent that there has been a refining of our translational hypotheses and a focus on, I would say, you know, large problems that we can solve with our small molecules. I think there is an aspect of how we're expanding the platform with both E3 ligase and molecular glues, that admittedly, we haven't shared much publicly, but I think it would be... should be on the lookout, because, we're using those opportunities in a very interesting way. And again, following the same path of going after these high-value undruggable targets. Hopefully, you know, we can meet again, this time of year in this conference, and I think the company will feel quite a bit different then.
Understood. 30 seconds left. I'll ask you one final question. On the topic of molecular glues, could you just outline for us. I know you're not in a position right now to discuss heavy specifics, but what indication set, what opportunity set does that modality offer that more traditional targeted protein degraders don't?
I mean, we, this is a very technical answer. We use heterobifunctional degraders when we can find a small molecule ligand to a protein of interest. We believe that is by far, still the best way to deploy the technology. It's a targeted, specific, much more rational and controlled. When you cannot find a small molecule binder to a protein of interest because it's a disordered protein, then the only way to elicit degradation is to create a protein-protein interaction through a new surface using molecular glue.
We have a really cool program where we're degrading a completely disordered transcription regulator, and that there would be no way to do with a traditional heterobifunctional molecule or let alone a small molecule. Actually, we're taking a much more of a probably disease area indication unbiased approach there, because it's really solving a technical problem, staying in areas of high, again, high clinical impact.
Understood. Great. We're at time, so we'll wrap up there. Nello, Jared, thanks for your time. Really appreciate it.