Okay, welcome to the Wednesday afternoon session. It's Wednesday, right? Yes. My name is Chris Shibutani, member of the research team, along with my associates. We are very excited to have Kymera join us this year for the 44th annual Goldman Sachs Healthcare Conference. Here, we have on the podium with me, Nello Mainolfi, Founder, President, and CEO. Lots of titles here. Then hidden off in the audience, Bruce Jacobs, the Chief Financial Officer. Bruce, we see you. You can only hide so long. The team that's out here, obviously, is coming at this meeting at an exciting time. There's folks, Jared Gollob, your Chief Medical Officer, is very busy at some medical meetings because you guys have been super busy, a lot of progress points.
We wanna make sure that we talk about some of the data reveals and new information that we've had today. I did also wanna just make sure that we talked about sort of like the partnership communications, 'cause especially at this event, there's been a, I think, very helpful, productive flow about all of these things. Maybe, Nello, just to start, get the transcript going off on the right page, give us a snapshot on Kymera.
Great. First, Chris, thanks for inviting us.
Of course.
This is our first time, actually, at Goldman Sachs. Last year, we couldn't make it last minute. Honored to be on the stage with you.
Glad to see you.
Kymera, just a quick, very quick introduction. Kymera was built in 2016 to take the targeted protein degradation modality into a fully integrated commercial stage company. We feel the responsibility to do this and to do this right. We feel it's important to make sure we select the right targets to go after with the technology. We wanna make sure we make the right compounds to put into the clinic, and we'll discuss that in a few minutes, I'm sure. That we develop the right development plans to make sure that patients have access That the molecules access the right patients, and in the market, they access the right patient population. We've focused for the first few years in oncology and immunology.
We found that, being disease-agnostic is where this company will go, but being focused early on is a way to build credibility for an early company.
Mm-hmm.
We are paranoid about target selection at Kymera, as much as we're paranoid about clinical translation. We believe that we wanna work on targets where only protein degradation can unlock the biological and clinical value. We also believe strongly that protein degraders are small molecules, but are also different. They behave differently from small molecules, so they have to be developed as protein degraders.
Mm-hmm.
We have a talented, as you mentioned, chief medical officer, that has been focused on how do we translate these programs into the clinic, thinking about the right dosing paradigm, the right regimen, the right degradation profile. We now have four clinical programs. We have a KT-474 that we're about to initiate phase II with Sanofi. We believe that is a small molecule, broad anti-inflammatory drug that has broad potential. We have three phase I oncology programs, an IRAKIMiD program for MYD88 mutant tumors, a STAT3 program for liquid and solid tumors, and an MDM2 program, also for liquid and solid tumors, that are reading data in the next few months. We're well-capitalized as a company.
We have more than $500 million that will allow us to get into the second half of 2025, more importantly, will allow us to read, we believe, many of these data readouts, going from KT-474 all the way to, the earliest oncology clinical program. You know, we're excited about also continuing to innovate. We believe that, you know, when you stop to innovate, you're starting to die already as a company. So novel E3 ligases to do selective degradation, novel molecular glue to go after unligandable targets, novel programs in small molecule immunology, which is where the future of immunology will be.
Mm-hmm.
Where protein degradation is best suited for. That's an exciting time for Kymera, I'll pause here.
Yeah.
-we can go into-
No, that's a tremendous overview. I think for investors, the whole notion of targeted protein degradation, TPD, as we often refer to the acronym there, if you've seen one company, you've probably seen one company. While, you know, the genus is the same, there's proprietary capabilities, and as you can be disease and therapeutic area agnostic, that is also true. It really represents a whole pathway towards addressing, therapeutically, many different targets that just, to this point, haven't been drugged before. The opportunity set is quite expansive. What is proprietary to you guys is your discovery platform, Pegasus. Just tell us a little bit about what makes that an element of Kymera's special sauce, because you said you're paranoid about target selection. Pegasus plays a role in tandem with all of that thinking.
Yeah. Yeah, I would start with, you know, we think about drugs as the end game of everything we do. We are fortunate, I think, to be in this place and time, where we can use a novel modality to develop novel drugs. I always say, "You're only as good as the target that you choose, but at the end of the day, you're also as good as the drugs that you make." Our platform is really focused on building the best drugs for the most difficult targets within validated pathways. Part of our secret sauce, let's say, it's, you know, again, how we select our targets and the type of criteria that we use. How we identify ligands for these difficult-to-drug proteins.
You know, we're the first company that developed a transcription factor degraders against STAT3. We have others in our preclinical pipeline that we will disclose soon. Our platform also enables us to use high content technologies to understand patient selection. Our platform allows us to identify novel E3 ligases that we believe can unlock a whole new generation of targets. Right now, the targets we're in the clinic for, are targets that can be degraded broadly. What novel E3 ligases that have different expression will allow us to do, is to degrade targets that where it's necessary to spare particular tissues. For example, you know, there are programs where we might wanna spare neutrophils.
There are programs where we might wanna spare cardiomyocytes, because on-target activity of that particular target will give unwanted pharmacology, while those targets have profound activity in anti-tumor context. We spend a lot of time, and I would say money, to identify expression profiles of these E3 ligases, together with Max Planck Institute in Germany. We spend a lot of time and money to try to identify now ligands to those E3 ligases. We're fortunate enough that we have several programs now, after, to be honest, years of investment, that can be directed in a sparing manner to tissues. You know, I think now we talk a lot about ADCs in the space.
Right.
I think it's the new hot thing. What is an ADC? It's a, it's a drug that is trying to select a particular cell population and spare others and increase therapeutic index. I think that using tissue-restricted or sparing E3 ligases is actually an elegant and more targeted version of being selective for the tissues that you wanna go after.
Mm-hmm.
The other aspect of our platform that is more recent is, you know, using molecular glues to degrade targets that are technically unligandable. Disordered proteins, disordered, non-ligandable transcription factors, those are ones where you cannot find a specific binding event with the heterobifunctional molecules, but you can find a protein-protein-enabled molecular glue degrader. We've been fortunate to identify a completely novel background that allows us to target many new targets, especially in immunology, with that particular technology. We'll be talking about that, hopefully, soon enough.
Yes, absolutely. Let's keep to the most recent things and those that are actually very much in your control, the wholly owned opportunities. Oncology-directed, two assets, KT-333, STAT3, KT-413, IRAKIMiD. We'll spend a fair amount of time talking about this. You know, if you had to think more broadly, just before we go into some of the details there, about protein degradation, and you've made reference to some of these elements, versus other modalities for oncology indications, what becomes your view of why there could be a particular advantage to taking this approach over sort of existing modalities?
Yeah, that's a great question, Chris. Let's talk about STAT3 for a second. STAT3 transcription factor in the JAK-STAT pathway, one of probably the most validated out there.
Yep
There are 25, I believe, 25,000 publications on the role of STAT3, and if you believe them all you need to drug is STAT3, and you've solved all diseases of humankind. Obviously, what I meant to say by that is that it's been studied, extensively studied in many contexts, in oncology, in liquid and solid tumors, in immunology and fibrosis, and in many other areas. It's clearly one of the most interesting transcription or, I would say, protein out there, that has escaped any real drug discovery effort for a simple reason: it's a transcription factor that is difficult, if not impossible, to drug with a small molecule, selectively. It is in the cell, so impossible to drug with an antibody.
It is a transcription factor that is broadly distributed, so difficult to drug with an oligo-based therapeutics, that so far have been limited with particular tissues. For that reason, for 20 years, it's not been drugged or drugged selectively or fully. When we started the company, IRAK4 and STAT3 were the first two programs that we went after because they represented two key principles of protein degraders: targeting a protein that has multiple functions, that the only way to address, you have to degrade it or knock it down.
Mm-hmm.
STAT3, which is a transcription factor that cannot be addressed with other technologies, you can bind to STAT3, and you can degrade it, but you cannot inhibit it. That's where we believe is, you know, the value of this technology. you know, STAT3 data that we shared today-
Mm-hmm
it, for me, especially, it's so exciting because it continues to prove why this is such a great target for protein degradation?
Yep. Let's talk about KT-333, and just tell us a little bit about sort of the compound there, and in particular, how it's administered to patients, and then we'll talk about the various unveilings of data sets. There were some abstracts, the ICML meeting, but first, identify the compound for us.
Yeah. Again, opportunity broadly in many disease indications, so this is a pipeline in a target. For oncology, we identified preclinically tumor types that were very sensitive to the presence of STAT3, so much so that as soon as you removed STAT3 at roughly 90%, you would see a rapid commitment to apoptosis, and cells will die and tumors will melt in these preclinical models very, very quickly with infrequent dosing. We actually realized that you only needed to degrade STAT3 for about 48 hours at that 90%, in order to drive strong antitumor responses. That's how the program was developed.
We went into the clinic, in the summer of 2022, with a goal in phase I dose escalation to obviously demonstrate PK/PD safety, identified an MTD, and ideally being able to demonstrate that we can reach this 90% degradation with a good safety profile, and also ideally identify in the patient population that we were dosing, patients that were sensitive to these particular mechanisms, in terms of ability to demonstrate antitumor effects.
We've often talked about how this is a year of revealing more of the clinical profile, and in particular, today, at the ICML meeting, we had a larger denominator of patients. We went from eight, that was available in the abstract. The cutoff now takes us to, I believe, the start of May.
Yeah
we have a larger denominator of 13 patients. Maybe you could recap the announcement that you made and the data that was presented at that meeting.
Yeah, for 333, we presented. Actually, the poster is presented on Friday, I believe, but it was up in the room today, so we obviously disclosed it today. You know, exciting data. First, I want to say that, for both KT-413 and KT-333, both programs, we shared updated data today. Now I can say that for three programs, for all the three programs that we've brought it to the clinic, KT-474, KT-333, and KT-413, we've been able to demonstrate that our drugs behave in the way they were designed preclinically, both in terms of how they're dosed, how they degrade the target, the PK that they have, and the safety that they bring with them.
While we may take a lot of that for granted, for a new modality and for people like us that work at the front edge of that modality, we know we don't take this lightly. We're very excited about having been able to demonstrate that for three programs, across many indications and disease types. What we shared with KT-333 today, as you said, 13 patients' worth of data. We've shown, in terms of PD, Dose Level 1, 2, and 3, we had showed Dose Level 1 in December, and now we've shown that basically with dose escalation, we are nearing the 90% number that we believe is important to drive antitumor responses.
We have seen really benign safety, and we're very encouraged that now as we're approaching, at or approaching, clinically active doses, we can start to really focus on antitumor responses. This is something we decided not to discuss today. As you see, we've recruited to the study both liquid tumor and solid tumor patients. We've shown preclinically that T cell lymphomas are those patients that preclinically respond very well to single-agent activity, so we expect to see single-agent activity from those patients. But we obviously recruit more broadly to the study to evaluate safety as well as PK/PD. For today, it was really demonstrating that we're close to or at clinically, what we expect to be clinically active doses based on the degradation profile, and that safety continues to be really encouraging for this program.
I would say it's fair to characterize that you're seeing nice dose response curve with the dose levels that you're showing so far, dose DL 2 and 3. Data also seem to suggest that you're getting increased levels of degradation as patients remain on treatment for longer.
Yeah
Particularly as you move into later cycles. Talk to us about those kinds of parameters, which thus far actually, are going in the right direction and quite promising.
I think it's obviously great that we see dose-dependent degradation. I think it's important that degradation is supported by dose-dependent increase in exposure by the PK, so that PK and PD are correlated. Another aspect that is worth highlighting that was in the poster, and it's also on our corporate deck on our website, that we also measured pathway biomarkers. Not only we're showing that we engaged the target and we degraded, but we're also showing that downstream biomarkers are modulated. In vivo, in patients, we actually were able to show reduction of CRP, for example, in circulating C-reactive protein, and also in genes. In transcriptomics, we were able to see reduction in SOX9, which is a gene downstream of STAT3.
At levels, again, in a dose-responsive manners and in levels that are comparable to the degradation profile. That's important not only for the development program of KT-333 in oncology, but as you know, we are expanding the STAT3 program also outside of oncology.
Mm-hmm.
The data that we've shared today, you know, is actually quite meaningful. Very few drugs are able to show this level of reduction of systemic inflammation, biomarker, as this drug has, with even 50%, 60% degradation as, you know, the initial doses. It's very exciting data, again, confirming that the drug is doing what it's supposed to do, which is really the key aspect of our update today.
The specifics of the regimen. This is stuff you're learning now. This is the purpose of some of this fundamental work here. you know, talk to us about how you might be contemplating either a weekly dosing regimen versus perhaps every three days or something twice a week.
What we've seen preclinically, as I mentioned earlier, that what's necessary and sufficient is about 48 hours of 90%, roughly 90% degradation of STAT3, to drive profound antitumor response. What we wanted to demonstrate... Then you can actually see the target recover, so much so that actually preclinically, both once every week and also once every two weeks, was sufficient to drive strong antitumor effect. We went into the clinic with once every week to actually be, I would say, more conservative, meaning giving the drug more opportunity to be active. We also know that full degradation of STAT3 and 90% 24/7 it is not really well tolerated, so we need to see some target recovery.
You know, usually we see some GI effect if we have targets knocked down constantly. That's why that pulsatile dosing is sufficient to drive antitumor activity and also well tolerated, both preclinically and now also clinically. In fact, I think something that I wanna point out, which we're learning in the clinic, we're seeing really strong target knockdown for five of the seven days. It's only really in the last two days that you see target recovery, which is a really important point for both activity and safety. We're seeing that the drug is quite active at degrading STAT3 for a prolonged period of time, but also well tolerated, which is really great for both our oncology program and also programs outside of oncology.
I think one of the common themes, typically with the clinical development of all of your assets, has been this notion that the adverse event profile is quite benign. Obviously, we're doing different dosage levels. Do you think that we're at certain levels? Would we be anticipating to be more mindful of that, perhaps, as we get into higher levels of dosage? You're seeing on the efficacy, the kind of kinetics and response that you're looking for. In particular, I guess, if you could just touch briefly on why one of the principal investigators did consider a squamous cell carcinoma, the skin in CT, the CTCL patient, was considered treatment-related. Help us understand.
Yeah
how we should interpret that observation.
Sure. I mean, first, obviously, that's not something that, we have seen in the extensive studies that we've done. That particular patient has, o bviously, as I had this disease for many years, a few years ago, was treated with UV light, for, you know, the skin manifestation of the disease. UV light does tend to, actually cause, carcinoma.
Mm-hmm
of the skin, and in fact, these patients for years before being on treatment, has had carcinomas that were treated. They would come and then obviously be treated, and then they would reappear again. It just happened that while the patient was on the study, this carcinoma reappeared, and obviously, they were treated. The investigators, because that happened while the patient was on study, thought that you would define that as possibly related. Actually, that's how they were categorized, possibly related, because they could not be fully ruled in or out. They were due to the patient being on treatment.
Because of the long history of this particular patient, we, you know, we don't look at this particular event as something that we're overly concerned about.
As we think about continued progress, more work to come here, enrolling more patients, advancing towards, is it reasonable for us to contemplate Dose Level 4 and 5? In particular, when we think about the patient mix, I believe thus far there's been two patients with CTCL, one with PTCL. Help us have some perspective in terms of where we are in terms of thinking about the total scope of the patient.
Obviously, you know, we had actually 1 CTCL patient on Dose Level 1 on Dose Level 2, 1 PTCL patient on Dose Level 1, mostly have been solid tumors. This study is open to liquid and solid tumors. Obviously, our investigators know what are the preclinically, the indications and tumor types that are very sensitive to single agent activity. As we've said, these are the CTCLs, the PTCLs, the LGL leukemias. As we are now nearing or at clinically active doses, I would expect that the investigators will prioritize those type of tumor types, because we believe it's that is where patients will have higher probability of responses. It'll be good for, obviously, patients as well as for us to evaluate the antitumor activity.
Okay, terrific. That's very helpful. We're obviously data junkies, always hungry for more updates. What should we expect in terms of the next time point? I know it was just today, and the poster is up, and the real presentation is tomorrow, we're already looking ahead. What's a reasonable timing framework and, you know, for the next installment of learning.
Yeah
about KT-333?
I mean, you know, we. As you know, the cutoff date, which was early May, we had, we have shown Dose Level 1 and 3 data. You can imagine that we've continued to recruit on the study, and focus also on patients that hopefully, you know, we expect to see antitumor activity. The next update will be, you know, in the second half of the year, probably towards the back end of it, and where we'll be able to tell the more comprehensive story, obviously, the full story on PK/ PD, and safety, but in this time, we will also be discussing the evaluation of antitumor activity.
What I would say is that the fact that we haven't discussed it today, does not mean that we have not seen antitumor activity. We decided to leave that conversation for a broader data set.
Okay, great. Let's go on to KT-413, IRAKIMiD. Just give us a snapshot of where we are with that asset.
KT-413, we had an abstract that published on the 9th also at ICML. We did not have a poster, but we decided to update it today also on a press release and also on our corporate deck on our website, I encourage people to look it up. On that particular program, we're also at DL 4, and we've shown now that at Dose Level 3 and 4, we have reached levels of degradation that we believe, based on preclinical data, we should expect antitumor activity in MYD88-mutant patients. If you looked at what we've shown, we've shown 50%-70% of the study IRAK4 degradation, Dose Level 3 and 4, and 90% + for Ikaros and Aiolos .
That's the profile that we've seen to be extremely active in MYD88 mutant lymphoma. We have dosed MYD88 wild type patients in Dose Level 1, 2, and 3, and actually one patient on Dose Level 4 was MYD88 mutant. It's actually a good time to start recruiting those patients. Also for this program, we expect that we'll try and focus as much as possible on recruiting those patients, at least, you know, investigators know that we're at that particular key inflection point. We plan to also the next update in the second half of the year to be focused on the totality of the data, including antitumor activity.
How is patient enrollment going? As obviously, the identification of patients with the MYD88 mutation. Right now, our current denominator looks roughly about what, and where could it be, perhaps towards the end of this year?
I mean, it's tough for us to guide. I would say for KT-413, we had 1 plus 1, so we had one patient per the first three doses, and then on Dose Level 4, we started 3 plus 3. Now the denominator, I believe, is five. We had five patients through Dose Level 1 through 4. Now we will be dosing, as I said, three patients per cohort. You know, we expect to have many more patients than we have now at the next update. But it's hard for me to guide on the number because obviously I don't control patient recruitment.
Okay. The one patient who did have the MYD88, are you able to share with us and disclose what dose level that was?
Dose Level 4.
Okay, terrific. Safety profile, adverse events, how to think about that, when we would expect to see?
Yeah, I mean, also there, you know, the first dose-limiting toxicity that we saw in our GLP talks was neutropenia, as you expect from the IMiD biology. That is a biomarker of engaging the IMiD substrates. We have done a lot of work in non-human primates to identify the degradation profiles, the dosing paradigm that would minimize neutropenia and optimize clinical activity. We're happy to report that we had no DLT, we had no neutropenia in any subject on our study that was deemed to be drug-related. You know, generally, the drug was well tolerated. As you've seen, we've reported the most relevant data on our corporate deck.
The usual Wall Street question: When can we learn more? I think phase I-B has to get kicked off. Give us a sense of some timelines of here.
Yeah, I would say for both programs, we are planning to have the next update in the second half of the year. Again, I would say for both programs in the back end of it, in a medical meeting, where we'll try and hopefully be able to kind of talk about the phase I-A study.
Mm-hmm.
Kick off the phase I-B early next year, and hopefully recruit the expansion cohort quickly.
Okay. we're gonna see if we can avoid having Bruce make it December 14th, annual Kymera-
Yeah, yeah, no.
Sort of, like, keep the stress levels high as we head into the holidays. I guess maybe every other year we could do that.
Yeah, we will try actually not to do that.
Okay. speaking of stress levels, I've been running around, actually fortunate to be able to talk to a whole spectrum of biopharma companies. Sanofi today was one of our folks, clearly a very important partner, and the commentary that Bill Sibold, who's of the, of that division there, reciprocated in terms of talking about the importance of the partnership here. I think there was genuine enthusiasm as he described, KT-474, IRAK4, a degrader. The announcement that was made, that you were able to share with everybody at the end of last year, was their intent to take programs into-
Yeah
phase II. Important for me to clarify, both for the transcript and those in this audience today, Bill apologized after stepping off the dais that he had said, "Yes, we're going into both of these programs next year." Actually, I think it's been clear and consistent in their actual communications, and IR was very quick to recognize this, that the HS study is on a timeline to begin during this year, and the AD is a program that they're enthusiastic as well. Just a little bit in terms of.
Yeah.
474.
First, thanks, Chris. You know, I actually had some time to look at the transcript. Obviously, we reciprocate, you know, the excitement. First, I will say Sanofi has been a great partner for Kymera. We've had a few partners along the way. We understand how collaborations work. They've been collaborative, open, and enthusiastic about this drug. We are both super excited about the prospect. The phase I data that we released at the end of 2022, sorry, was exciting, above and beyond our expectations. We and Sanofi have done our best to accelerate the development of this drug. We are excited to start the HS study in 2023, as you've just said, that Bill had meant.
We're also happy to say that the second study will probably start quickly thereafter. I can't really guide on exact time, but I think what Bill said, that both studies will be active in 2024, was a fair comment. More importantly, we're very excited about what this drug can do for patients with inflammatory diseases. I think in many of these diseases that we're planning to go in, obviously HS and AD, we've decided that will be the first two, but we're thinking about what's beyond. These are all diseases that lack a small molecule oral drug with a good safety profile. The opportunity here is vast, and the biology of IRAK4 is broad anti-inflammatory drug that has a pleiotropic mechanism impacting plethora of cytokines and chemokines.
We're all very excited about being able to generate phase II data as safety.
Exactly the scope of the opportunity, the sheer numbers of patients, obviously, DUPIXENT is the golden goose for them there, just a dominant presence and expanding across multiple different indications. If you could just help us with your point of view on potentially where it could fit. HS and AD are very different types of diseases in terms of one being a little bit more niche. Just to set the stage for us, where would you contemplate where KT-474 could fit?
Yeah. First, I would say that this is gonna be my commentary.
Yes.
It's not gonna be Sanofi's commentary.
Understood, right. They have their strategy and their.
Yeah
underlying motivations as well.
Yeah. I would say, first of all, actually, HS is a growing, it's a growing disease, not because the disease is growing, but I think our ability to help patients with HS is actually bringing more patients.
Mm-hmm
diagnosed with HS. That almost reminds me of the early psoriasis day, the early AD days.
Sure.
I would, again, give also credit to Sanofi for actually having a drug that has brought AD to the front stage, because there was a drug that was active in that disease. I think IRAK4, for the type of mechanism that it has broad potential in Th1 inflammation, Th1/Th17 , so HS RA, obviously, we expect to be active there. Again, I'm not saying that's where we're going, but this is where the drug could go. HS, as I mentioned, RA, IBD, Lupus, these are all indication in Th1, Th17, where there is a biological overlap, there is a clear unmet need, and there is a clear commercial opportunity.
In Th2, where we've shown already early data in AD, you can imagine asthma, COPD, or other indications where a drug like KT-474 could be active in.
Mm-hmm.
I think actually the teams in the collaboration are discussing what, you know, the next step would look like, but I think it's premature for us and for me.
Mm-hmm
-to comment for the collaboration. I would just say personally, obviously, we built this program because of the breadth of opportunity.
Exactly.
Obviously, we didn't build the program just for HS and AD.
Right.
Although those would be amazing opportunities, already.
Yeah, no, I think a smart decision, clearly a blue-chip, dominant partner in that with all the insights that's available. We're past our time here. I'll just close to make sure and the capable stewardship of Bruce Jacobs as the CFO. Remind us what the balance sheet and what you feel your, you know, financing support is, gives you run rate through. Is there anything on the numbers?
Yeah, I mean, as I said earlier, we have about $516 million as of March. That will allow us to get into the second half of 2025, will allow us to read many of these studies that we're talking about, 474, 333, 413, 253, our MDM2 programs that we didn't get the chance to discuss this time. We expect to bring at least another three to four programs in the clinic in that runway. It will be a different company by then.
Yeah.
Completely.
Absolutely, we'll look forward to that. The definition of platforms is that flywheel effect, generating additional assets. I wanted to leave more for additional conversations, we'll look forward to all the clinical progress. Nello, thank you for joining us.
Thank you, Chris.