Okay, perfect. Welcome to the second day of the BofA Healthcare Conference. I'm Geoff Meacham. I'm the Senior Biopharma Analyst here. We're thrilled to have Kymera with us, and on stage with me is Nello Mainolfi, who is the Founder, President, and CEO. Got the name right?
Perfect, Jeff. Love it.
Maybe to kick it off, Nello, give us just a high-level view here and just talk through kind of targeted protein degradation and kinda where you guys sit.
Excellent. First, Geoff, thank you for inviting us. This is a great conference. We love being here, and you guys do a really great job. Protein degradation it's the only new small molecule-based drug modality of the past, really 50 s. It gives us an ability to address the 80% of the undrugged proteome that we're not able to address with existing modalities, whether it will be small molecules, antibodies, oligo-based therapeutics. In principle, has the potential to really change how we think about treatment paradigms. It does it at a really the high level with a very simple concept. You use small molecules to bring disease-causing protein to the ubiquitin proteasome system, which is really the disposal mechanisms that our cells use to get rid of proteins.
You can do that very selectively, very rationally designed. It's disease-agnostic, tissue-agnostic, target-agnostic. Really the, I would almost say sky's the limit in terms of opportunities. It's our responsibility, not just an opportunity, to deploy against the right type of targets, the right type of diseases, the right type of patients to maximize value for patients first and then for everybody involved.
Perfect. Let's talk about four-seven-four. You know, just walk us for those that may not be as familiar, where you are in the clinic, and then we can talk about the QT thing. We finally, I think of put that to-
Yeah
...to bed.
Yeah, no, thanks, Geoff. Maybe I just take a moment to highlight. Just concept of protein degradation that we just covered. Kymera was founded in actually now seven years ago with the goal of building a commercial stage, fully integrated biotech that will fully capitalize on the power and opportunities of the technology. We have four programs in the clinic, one in Phase II and three in Phase I. While obviously we made a lot of progress, we've executed really, really well, we have a great team, we're still very early versus, the promised land of being a company that commercializes its own drugs.
Obviously, you have to go through the stages, so it's important that we continue to invest on the right targets, deploy capital against the right opportunities, and be, as I like to say, brutally honest with how we interpret any data that we generate. Our first program, going back to your question, Jeff, our first program that entered the clinic actually a couple of years ago now, is KT-474. It's an IRAK4 selective degrader for a wide variety of autoimmune diseases. IRAK4 is a central node in the IL-1 TLR pathway. Degrading IRAK4, unlike inhibiting the kinase function of IRAK4, there are other companies before us have done, gives you the opportunity to fully block the inflammation driven by IL-1 TLR, IL-1 receptor, TLR receptor activation.
We've shown pre-clinically extensively, but now also in Phase I in both healthy volunteers as well as patients with HS, hidradenitis suppurativa, and AD, atopic dermatitis, that degrading IRAK4 gives you an opportunity to see meaningful clinical benefit in patients through an ability of full degradation of IRAK4 in blood, substantial degradation in skin, and impact on a broad series of cytokines and chemokines. The program is partnered with Sanofi, who is responsible for Phase II and beyond. We have transitioned the program in their hands since December, when they decided to take on the program into Phase II and beyond. We will announce Phase II start when that happens, as we said, also as recently as few days ago.
Right. Just on the on the safety tolerability profile.
Yeah
...looking at sort of the more recent kind of updates.
Yeah
on the QT thing.
This drug has been actually tested in close to 150 subjects in Phase I. It's been a typically comprehensive Phase I for a lot of reasons. We also believe that for a new modality, you really have to do a comprehensive job, especially in the early translation. We've demonstrated that the drug is really well tolerated. I t's again, it's been tested in multiple subjects, both healthy volunteers and patients. There hasn't been any serious adverse events. The only adverse events have been mostly mild in nature, like headaches, in some case, nausea.
What we've uncovered that Jeff is referring to in the healthy volunteer 14-day study is subclinical, non-dose responsive and non-adverse. Prolongation of QT, again, slight 10-20 millisecond. We've also seen that when we went into patients and went from 14 days of dosing to 28 days of dosing, we saw that with continued dosing from day 14 to day 28, this again, subclinical QT prolongation resolved spontaneously. Much that by day 28, the QT was back to baseline. Basically, we've uncovered this subclinical transitory signal that is only apparent around day 7 and starts going down already, again, by day 14 and completely resolves by day 28.
While even in the presence of the early understanding, we were working under the assumption that it would have no impact on how we were thinking about development of the drug. With the, again, spontaneous resolution, we don't believe this is something that is of any impact on our plans.
Right. Perfect. Sanofi is going to initiate the HS study. Talk about kind of what, what does, success look like there? Maybe just at a higher level, Nello, talk through kind of how you view the risks of investing in the, kind of the I and I space versus hematology, oncology.
Yeah.
You know, you have different parameters and different acceptances of safety tolerability.
I mean, I would say that we were the first company in protein degradation to invest outside of oncology, within both small and large companies. We believe that, and we still believe, that the future of immunology is small molecules. Right now it's dominated by antibodies, but the future is small molecules. In order for the future of immunology to be small molecules, you have to have really active, well-tolerated small molecules. We saw that the opportunity of this modality to degrade protein and provide unprecedented biology was a way to transform the immunology space. We were in immunology when immunology was obviously fascinating and interesting and, large opportunities, but obviously not as hot as it is today where everybody talks about immunology.
We were, let's call it, fortunate enough to think about immunology early in the stage of the company. We're well aware that it's important to have pristine profile when you're in immunology, and we have no reasons to believe that this technology wouldn't allow us to have, highly selective, well-tolerated drugs. We totally believe that that's doable with protein degradation. Actually it's a feature of protein degradation, high specificity, high selectivity. We will continue to invest in both immunology as well as oncology. If you see on our website, on our corporate deck, we have several programs that are preclinical at this stage that are designed to unlock novel immunology mechanisms as well as novel oncology mechanisms. We will continue to do so.
We believe we have the know-how, first-in-class know-how in immunology to continue to drive value there. Going back to this, the question on Sanofi on HS. We, as we've disclosed in December, the collaboration, Sanofi and Kymera have prioritized HS and AD for the first Phase II studies for KT-474. That does not mean that those are the only two indications where this drug will be developed. This only means that they're the first two indications. We believe that with continued tractability and with continued data, there are many other indications that are being actually right now prioritized to eventually develop this drug. As we talked about timing.
We know that, HS will be the first indication and followed by AD, not in a sequential manner, but in a staggered manner. We're excited about generating, again, first-in-class data in a placebo-controlled, manner, unlike obviously the Phase I study that we ran.
Yeah. HS is a bit more of an unmet need. I wouldn't say atopic derm is not an unmet need, but it's just, it's a pretty competitive field at this point, right? How do you think about, product differentiation at the Phase II level?
Yeah. I mean, in HS, so far in the US, only Humira is approved. I think there will be more drugs approved probably in the next couple of years in HS. AD, we really have a pretty impressive drug that Sanofi has, with Regeneron, has done a great job developing, which is Dupixent that, probably will become the number one drug in the world in the next, I don't know, couple of years. Let's remember that both, Humira in HS and I would say even more Dupixent in AD, have limited penetration in that patient population. I think Dupixent right now is in around the 8%, 6% or 8%, I don't remember exactly.
Again, in HS, Humira works, but not as well as we would like. There are no small molecules approved with a good safety profile in any of these indications. The opportunity is to continue to generate data that demonstrate clinical activity, good safety profile, and then I believe we have huge opportunities both to help patients, to provide them with a simple oral options to these complex diseases, and also obviously commercially, given the unmet need and the large opportunities. I don't think, I think of, I think competition is important because patients need alternatives. There is no single drug that will solve any immunology disease, as there is no single drug that solves any oncology disease.
It's about providing a drug that will help patients in their treatment paradigm and allow them to have a convenient and active drug for as long as possible.
Nello, do genetics tell you anything about patient populations that are, more at risk from, protein, degradation sort of malfunction when you look across the spectrum, right, of what immunology indications you can go after? Usually you see that in oncology.
Yeah. Yeah. Like where does human genetics sit in immunology? T his is where immunology will move, right? Will move into patient stratification. I think every company, we included, are working to understand and to increase basically probability of success, as we've done in oncology. If you have a responder population, you wanna focus on your responder population. It is fair, especially for IRAK4, where we have a pleiotropic broad anti-inflammatory signature, we probably can be a bit more ambitious in terms of percentage of population that we can, that we can serve, because we impact so many cytokines and chemokines, IL-17, IL-23, TNF, interferon, TH2, TH17 biology. we have really a broad opportunity. Nonetheless, understanding where, the responder population lie is important.
I think, we know human genetics as pointed to diseases where some mechanisms are more suited for. I think TYK2 is a good example of, the human genetics. IRAK4 has shown strong human genetics on safety and obviously also human genetics experience in terms of other diseases. We have other programs in our pipeline in immunology that we haven't disclosed that follow probably much more human genetics and clinical experience than other, maybe other companies right now. It's obviously an area that is going to require still a lot of investment. Protein degradation is the closest out of all technologies out there to mirror human genetics than any other technology. I've already said that.
Keep an eye on protein degradation in immunology, because that's what is going to, I think, really change how we think about treatment paradigms.
Gotcha. Well, coming up, you guys should have data for four one three and three three three, safety and degradation results. You know, give us some perspective for how to, how do we benchmark this? What does sort of success look like? How do we think about the products in advance?
Yeah. Maybe I'll just do a brief history here just to make sure that the communication is clear. KT-413 is a so-called IRAKIMiD degrader. It degrades IRAK4, Ikaros, AI, and Aiolos, and we found that if we degrade IRAK4, Ikaros, and Aiolos, we're able to generate a synergistic signature in MYD88 mutant tumors. MYD88 mutant tumors are MYD88 mutant lymphoma, diffuse large B-cell lymphoma. About 25% of patients with diffuse large B-cell lymphoma have this mutation. About 90% of Waldenström's patients have this mutation, and about 70% of primary CNS lymphoma have this mutation. It's a sizable, well-characterized population. Our dose escalation is in broad B-cell lymphomas, so we're not selecting for MYD88 mutation.
We showed in December, the first 2 dose cohorts, dose level 1 and 2, PK, PD, and safety. We've said in 2023 we should be able to dose escalate high enough in the active doses, which we believe are dose level 3 and 4, and bring to the study enough patients with MYD88 mutation that by the end of 2023, in the second half of 2023, we should be able to evaluate the antitumor activity of degrading IRAK4, Ikaros, and Aiolos in MYD88 mutant patients. The goal for 2023 is for us to evaluate the clinical activity. What does degradation of Ikaros and Aiolos do on MYD88 mutant patients? That's the goal for the year.
What we've said recently, and that's the goal that we believe based on where we are with dose levels, where we believe is our active dose levels, and the type of patients that we can recruit to the study. Based on these parameters, we believe we should be able to answer that question in the second half of the year. Going back to the question from Geoff, we have a presentation at ICML next month, actually, in June, where we're giving a clinical update on the study focused on where we are on our dose cohorts. During the year disclosures, if we're able to demonstrate that we're at or close to the clinically active dose, and where we are with safety, then it sets up the disclosure later in the year about clinical activity.
This is KT-413. For KT-333, which is a STAT3 degrader, actually, we showed dose level 1. Also in that particular case, we said that dose level 3 and 4 we expect them to be clinically active. For KT-333, a STAT3 degrader, which is really a broad program, we've seen pre-clinically that tumor types that respond to single agent are T-cell lymphomas, especially PTCL, CTCL, also LGL leukemia. In solid tumor, we've seen most activity in combination. We've seen with PD-1, and we've seen it also with other agents that we haven't disclosed yet. In our dose escalation, which is actually open to both solid tumors and heme tumors, the responder population is a subset of heme tumors.
For us to evaluate clinical activity, we need to be at the active doses and then recruit to the study enough patients from CTCL, PTCL, LGL. Also for that reason, we believe that between getting to the active dose and recruiting the right patients, this will be a second half of the year timing disclosure. Also ICML will update on where we are with the program, where we are with the type of patients that we've seen, and also with the PD and safety. It will be clear at ICML why we're saying that the disclosure is around clinical activity is the second half of the year. There will be no doubts why we're saying that. You know, speculation about lack of clinical activity, et cetera, will be clarified at ICML.
I think everything will be clear why we're saying this is gonna be a second half of the year. Sorry, this was a long answer.
A very long-winded. No.
hopefully it was comprehensive.
Yes.
All right.
Let me ask you, though, from a, sort of from a philosophical perspective, if you given the foundational nature of the mechanism, right, of TPD, have you found in, in cancer or other animal models or whatever, compensatory mechanisms that, can theoretically drive resistance down the road? I mean, it seems like, you should have a higher probability of response of, antitumor activity, given the nature of the mechanism.
Yeah. I mean, I would start with saying, that cancer will always, try to find a way. I think we should just be upfront about it. What I will say is that if you use a degrader versus a small molecule, you have much higher chance to overcome resistance mechanisms because you're actually removing the protein. You're creating less pressure on the cancer cells to find compensatory mechanism because if you're choosing the right mechanism, protein knockout through a degrader leads the cancer cell to an apoptotic response, which is what all companies should be working on with this technology because it will allow you to do that.
Now it's been shown, for example, Revlimid and its analogs that, in multiple myeloma a resistance mechanism takes place by changing the regulation of the E3 ligase in a way that makes the drug less active. We haven't seen that pre-clinically in our oncology studies. That does not mean that we won't see it in the clinic. I think maybe it just means that there is a lower probability. W e always have to be on the lookout for resistance mechanism. I will also remind everybody that even with the Revlimid, they've seen thousands of patients, if not more, and it's one of the most successful drugs out there that obviously it's a degrader in case I missed to say that.
The resistance mechanism and the resistance only happens in a subset of the population and still, t hat drug is still a hugely successful drug.
Okay. That makes sense.
This is why it's important, sorry, Jeff, to keep in mind there is nothing about protein degradation that speaks only to oncology. It's a great mechanism in oncology, but it's a great mechanism in so many other disease areas. W e're working in immunology. We'll probably be working in other disease areas. It's important that we expand beyond oncology. Just a little plug there.
Right.
for the space.
Right. No, that makes sense.
For whoever is listening.
Is it possible, obviously you could move in oncology perhaps a little faster than you in immunology, would you say? Once you get proof of concept Phase I antitumor activity and then perhaps go straight to a pivotal depending on the, if it's a more, a more narrow, tumor type?
I would say that, I mean, it's true that in oncology, even with, different regulatory let's call it an evolving regulatory landscape, I think it's fair to say that oncology still provides a potential faster path to approval. I think there are opportunities of very meaningful drugs in so many indications within oncology and outside of oncology. I think it's about picking the right target.
Yep.
Going after the right patients.
Lastly on 253, what's when you think about benchmarking, that same idea, right? I mean, just, evidence of.
Yeah.
Degradation, et cetera.
Yeah. I mean, I'm so excited about, starting to generate data soon with KT-253. S tabilizing p53 is being something that the biopharma industry has tried to do for, I don't know now, probably 20 years, since we discovered p53, which is the largest tumor suppressor gene. I think we got fooled, as has happened in many cases, that we thought that cancer genetics or knockout of MDM2, which really started this space, stabilizing p53 by knocking out MDM2 in p53 wild type tumors show this high dependency for so many cancer types. Then we assume that inhibiting MDM2, p53 interface would give you the same data.
We've learned the hard way that that's not the case, that inhibiting MDM2, p53 can be effective, but has limitations driven by, again, a MDM2 upregulation that cancer cells drive to really actually overcome these antitumor mechanisms. With a degrader, we can remove MDM2. Even if there is MDM2 upregulation that the cancer cell has, we can continue to degrade MDM2. We overcome the feedback loop, and we drive these tumor cells to rapid apoptosis. We've seen even in PDX models that a single dose of an MDM2 degrader, not inhibitor, degrader, leads to profound and continued response for several weeks. Showing that this is one of the most central mechanisms in tumor oncology, in tumor biology, that we're able to elucidate by using a degrader mechanism.
We're excited by the opportunities. I will say, not to spoil it, that this mechanism will not work in every p53 wild type tumors. That would be too good to be true. Really what Kymera is focused on is which p53 wild type tumors are so sensitive to MDM2 degradation that we can dose as infrequently as once every 3 weeks and drive complete responses as we've seen in preclinical species. We've shown a few already. We've disclosed a few. We've shown some double-hit lymphomas. We've shown AML, ALL, and we have a whole subset of solid tumors that we will be disclosing later in the year, early next.
Perfect. Just in the minute or so we have left, so just talk a little bit about from a high level, Sanofi is your partner. Looking forward, are you more or less likely to partner sort of either for strategic reasons or for, non-dilutive capital?
Yeah, great question. I mean, we wanna build a commercial stage integrated company. We are in pretty large spaces in both immunology and oncology, if you look at our pipeline. We will have most likely eight clinical programs in the next couple of years. I think it will be unlikely that we will be developing all these programs on our own all the way through the end and commercializing them.
That doesn't mean that we can't do it. I think it's about how you choose to use your capital. There might be, and I think it will be likely that there will be opportunities to find a win-win partner to maximize value creation. I like to say this analogy of I'd rather get a slice of a much bigger pie than a very small pie.
This is what we're trying to do with our programs, set them up for maximal value creation, and then there are some that we will take all the way. We've already decided, and we already know what they are. There are some where we'll have to figure out what's the best way to extract maximal value will be.
Great. Well, Nello, thank you very much.