America Conference. I am Tazeen Ahmad, one of the senior SMID biotech analysts at the firm. It's my pleasure to have with us our next presenting company, Kymera. Sitting next to me on stage is CEO Nello Mainolfi. Nello, thanks for making the trip out west to see us.
Thank you, Tazeen, for having us.
We're going to just start off with a couple of macro questions because I think it's topical, and you've probably had to answer this a couple of times anyway. Let's just get it out of the way. Can you talk to us about your interactions with FDA? More importantly, the more recent ones, let's say over the last couple of months, has there been any change that's noticeable either in who you're speaking with, topics of discussion, etc.?
You know, I will say that. Is this too loud?
No.
Feels too loud. I will say so first, again, thanks for having us here today. Obviously, we have several ongoing interactions with the agencies, both in the U.S. and outside of the U.S. We have not seen any material changes in our interactions. I hear that, obviously, and I see that there are structural changes and different hires, but we have not seen that, at least so far in our direct interactions, we have not seen that change materially.
Okay, that's good to know. In terms of we're thinking ahead, but in terms of where you plan to have manufacturing be, can you share with us any details?
You know, everything that we do is done in different countries. We do obviously a lot at Kymera in Watertown, Massachusetts, if anybody wants to come and visit. We source also some of our raw materials globally. Obviously, what we do for our—we're not a commercial stage company. We're a clinical stage company. We are committed to making sure that we source our commercial material in the U.S., at least the material that will eventually be commercialized will be done in the U.S.
For any portion that's not done in the U.S., do you have any, I guess, redundancy plans if needed to bring that onshore?
Yeah, look, I think this is a much bigger conversation. If we want to get there, the question we need to ask ourselves, do we have the infrastructure in the U.S. to support the biopharma industry in terms of manufacturing of drugs? The answer is no. It's a simple no. If we want to go there, Kymera will be at the forefront of the investments, and we're all in. Until then, we will continue to do what we need to do to protect our shareholder investments and manufacture where there is capacity. Right now, it's all over the world, including the U.S. I'll say it again, I'm a huge fan of bringing manufacturing in the U.S., assuming we make investments in basic research and in infrastructure.
Okay, good enough. Let's talk about some upcoming catalysts that the company has in the second, let's say, second half of the year. We're almost done with the first half. Maybe set the summary for us, and we can go into detail.
Yeah, so I think June is the first half, right? So the first.
Okay, the first half.
Just checking.
Okay.
Okay. Our first, the upcoming catalyst is obviously the healthy volunteer data for our KT-621 that is still in June. Obviously, this is a study that we've said has been completed recently. We completed dosing in March, actually, of the last MAD cohort. We are in the process of collecting the remaining data to being able to then present it. We've always committed to presenting the totality of the SAD and MAD data. We could have obviously presented some majority of the data already, but we feel like we're at the stage of the company where I think we want to do a good job, and we want to have one presentation instead of more than one. That's in June. Obviously, STAT6 is a very unique program, I would say, in this industry.
I think very rarely we've seen that one of the best blockbuster drugs in the world, in this case, dupilumab and alpha receptor alpha, has an intracellular target that has the potential to replicate the same profile. STAT6 being the selective transcription factor for alpha receptor, targeting STAT6 has the potential to have a dupi-like effect in an oral drug. It is expected that there is a lot of excitement and focus on it. We've talked extensively about our target product profile for STAT6, for our STAT6 degrader KT-621. I remind everybody this is the first STAT6 directed agent to be in the clinic. Our target product profile is a molecule that is able to degrade STAT6 and 90%+ in blood and skin and safely.
We believe if we're able to show that kind of profile, we would have de-risked the opportunity set for this asset tremendously, given how well the biology and the human genetics speaks to the relationship between IL-4/IL-13 and STAT6.
Okay, can you just remind us what dosing regimen you're testing in this healthy volunteer study?
As we've done preclinically, the drug is dosed once a day. The SAD and MAD is a single ascending dose, and then we'll have multiple ascending doses. The drug is dosed once a day for 14 days at different dose levels to evaluate, as I said, again, the safety, the PK, and the degradation of STAT6.
Okay, the topic of biomarkers has come up. Can you just remind us about which ones are being used? When the data comes out, how to interpret that?
Yeah, so the beauty about protein degradation that I think I want to make sure I spend a minute, if I may, on it is we've been used generally in the industry to look for a proximal biomarker to demonstrate target engagement. For small molecules or even biologics, usually a proximal biomarker can be a downstream chemokine, cytokine transcript in the nucleus. The inhibition of that particular downstream effect is a proxy for the target inhibition. That's historically how drug development has worked. The innovation that comes with target protein degradation, and that's true also for, for example, RNA interference drugs, you can actually measure a direct target engagement. Direct target engagement in our case is how much STAT6 do we degrade. Unlike, again, unlike other programs, we have a direct way to measure target engagement.
We know the association between STAT6, IL-4 and IL- 13. The most important biomarker for this program is STAT6 degradation because it's the most direct and significant biomarker. Now, from other studies, from other drugs, especially dupilumab, and this has been done a bit retrospectively, because actually they couldn't measure a direct biomarker, they looked at what can we look at in healthy volunteers that might be impacted by the drug. I think what probably the biomarker downstream of alpha receptor alpha that has a bit of a window to measure is TARC that dupilumab has shown activity on. They've also looked at IgE, but I will say TARC has a bit of a bigger window. The problem with these downstream TH2 biomarkers is that they are a biomarker of pathway activation. If you're in healthy volunteers, you don't have TH2 disease.
These biomarkers are a baseline in the normal level. When you give dupilumab and your top dose has a 30% reduction of biomarker, and that's not even dose responsive, you understand that it's a noisy, difficult to interpret biomarker. The reason why it's been discussed a lot is because there is data out there from dupilumab that shows that you can impact TARC in a range between zero and 35%, depending on the dose. What we've said, we're going to look at those biomarkers, we're going to report on the data, and we expect it to be in the same ballpark. I think what we're trying to caution against is trying to draw conclusions between these two drugs in two different studies with two different assays with different patient subjects when the baseline level and the assay window is so noisy.
I like to think about this drug as an oral dupi-like drug. And our expectation is that it's going to look like dupilumab.
Okay.
With all the caveats that I tried to explain, maybe not well.
Now I'm thinking about translating the results from healthies into actual patients.
Yeah, so that's the beauty of our development program, is that while we're still talking about healthy volunteers data in June, we've already started a phase I-B study in April. We've already dosed our first patient in April. We expect to have completed this study in the fourth quarter of the year. Now, the beauty about our study or any study in AD patients is the AD is a highly TH2 skewed disease, which means that the biology of IL-4 and IL-13 is very relevant in AD patients. Dupilumab in AD patients has shown that after 28 days of dosing, you can see a robust reduction, for example, of TARC. Now, it's not 0%-30%. It's actually, depending on the study, between 70% and 80%. It's a very robust and reproducible signal.
Even more importantly, in the skin of patients, in the lesions of AD skin of patients, you can actually look at pre and post-dose series of genes that are modulated by dupilumab. That signature of dupilumab in AD lesions of patients is actually well characterized. I think there is an appreciation that there is a high level of correlation between the depth of these transcript changes to EASI score. Given that these biomarkers have little or no placebo effect, we'll be able to actually now generate a robust data set in patients and be able to compare now with some level of confidence to the dupilumab data in 28 days. We'll be able to show, hopefully, biomarker changes in blood, in skin, and then tie them to clinical endpoints that are usually measured in AD patients, which are EASI as well as IgE.
Okay, I have a couple more questions on this topic, but I'm going to briefly jump ahead to the actual patient data that we might be able to see. Is it by year end?
Yeah, 4 Q.
Based on this data that you present, if you were to try to think about the likelihood of success of your patient study, would the likelihood of success increase if you saw STAT6 reduction, knockdown, degradation? And does there need to be a minimal amount of that?
Yeah, so thank you. What we've shown preclinically is that if you have more than 90% degradation, 90%+ of STAT6 in every model that we've run, both in human cells or in preclinical mouse model, we've seen an effect on both biomarker and disease endpoints that are at least as good as dupilumab. Our healthy volunteer data, if we're able to show that we can degrade the target robustly and hopefully safely, I think in my view, it's going to tell us that we're going to see some robust efficacy in patients because that's what the biology tells us.
Okay, and then just going back to what we were talking about, does it matter the level of degradation per indication? Would you expect to see have a minimal threshold for AD versus, let's say, asthma?
Yeah, I mean, it's a great question. The reality is that nobody knows the answer to that. I think the reason why we want to be able to reach 90% plus and safely is because we like to explore that profile in our phase II-B studies in both AD and asthma and probably go below and then assess whether in AD and/or asthma, there is a different threshold of degradation that leads to maximal efficacy. My guess is that it's going to be the same because I think it's about pathway blockade in TH2 diseases. I don't believe that in order to achieve maximal efficacy, you can get away with less than maximal pathway blockade. I think time will tell.
Okay, and then I also wanted to touch upon safety. We'll presumably get an update on the safety profile. I think the questions that are coming up on safety are more really about IRAK4 as opposed to STAT6 and whether or not you should expect to see anything similar for STAT6.
In which way?
Any kind of observation of safety concerns, at least initially.
If we go back to IRAK4, this is KT-474. This is back three, four years ago. We had a very good safety profile. The AD, I think we had mild AEs mostly. I think the most common adverse event was headache in their phase I study. Obviously, these are different drugs, different mechanisms. I do not expect that there will be any overlap of AEs because they are, again, different drugs and different mechanisms. I think the only thing I would say is that our translation of our preclinical into clinical for KT-474 was quite good. We hope that it will be the same with STAT6.
Is there anything inherent to STAT6 that you would be on the lookout for?
We've run extensive preclinical safety studies, TARC studies, I should say. We haven't seen any adverse events in those studies. We've also looked closely at all the human genetics. If you look at gain of function of STAT6, the only phenotype is severe allergic diseases. It's telling you that's the job of the protein. We've also looked at heterozygous loss of functions of humans that were identified a few months ago. Also, they were completely normal. Mouse knockout, normal. We don't have a particular thing that we're going to look out for. We would obviously look out for anything and everything, but we don't have a particular concern.
Okay, so no concern like for QT prolongation or anything?
No, so the QT, it's a good, sorry, reminded me for KT-474, we did see a subclinical QT effect in the 5-10 milliseconds. This was tied to an off-target effect for a really small mild binding to a HERG channel. We were able to actually replicate this signal preclinically. We did not see that signal in our IND- enabling studies because the, let's say, the FDA recommended models that we used were not sensitive enough to see the subclinical signal. We actually built a whole new model to measure that. We haven't seen that with any other drug. We have zero expectation that we see it for KT-621.
Okay, can you talk about what the competitive landscape looks like for orals for AD outside of Kymera and how you think it could be differentiated?
I mean, the only oral approved drug in AD is, I mean, obviously, it's a JAK inhibitor, which actually works quite well, but comes with the known both safety flags and the need for testing ahead of initiating dosing. That adds several layers of complexity. I haven't seen any robust data yet on any other oral drug. Obviously, we have our IRAK4 degrader that will have data in AD, placebo-controlled randomized data in AD next year. Obviously, there was recent data on the ITK, but it's like on eight patients, so it's a bit difficult for me to comment on. I think that there is no drug, though, that has a TH2 specific profile. STAT6 degrader is the only drug that is going to address only the inflammation driven by this pathway. I don't think there is any other drug that can do that.
Yeah, so the ITK I think you're mentioning is the Corvus data.
Yeah.
It had a 63% EASI-75 score, and you mentioned it's in eight patients. Based on your response, I think probably more data is needed to really understand how that could end up in the competitive landscape.
Yeah, I mean, yes. I mean, I'm not dismissing the data. I just feel like it's early data and we'll see. It's a very different mechanism. When we are blocking the inflammation driven by IL-4 and IL-13, we're not killing T cells. It's just a bit of a different mechanism. It's a BID drug. I don't think that that's going to be our direct competitor, but obviously, it's a big space. Hopefully there is an opportunity to expand the market by having multiple other drugs. I think it's all good for patients as long as they're safe and effective.
How important will it be for onset of action of your drug in order for it to be a competitive product?
Yeah, no, it's another great question. I think if you look at the biology of this pathway, you see that the onset of action is driven by, I assume, the pharmacology of IL-4/13 and by the biologics kind of onset of full target engagement. I think it's a question that we're curious as well. I think our expectation is that it will be a dupi-like effect, but that's why we're running the studies. We'll see.
Okay, so as we kind of move forward to looking at patient data, just remind us, is that going to be at the end of this year or would that roll into next year?
4 Q, yeah, 4 Q. Our expectation in fourth quarter of this year will have the phase I-B AD data.
How many patients would that be?
We are targeting about 20 patients.
Okay, and this is open label?
Yes.
What would be good there and how should we interpret that?
I think the expectation should be that it's going to perform like dupilumab in both biomarkers as well as efficacy. It's always difficult, obviously, to compare small data sets like just mentioned another company. There is always going to have to be a bit of mental flexibility to absorb data from different studies of different drugs with different ends. We feel that's why it's very rooted in biomarkers because biomarkers have little or no placebo effect. There is a very robust signature for dupilumab, and we don't have any reasons to believe that our drug will have a different type of biomarker signature. Once you have degradation biomarker and then a clinical endpoint, it's a really good story that can be used to evaluate the activity of the drug in early clinical development.
I actually like to think about this as the conclusion of the clinical translation, right, of you're taking a STAT6 profile that I would say it's widely accepted that preclinical is quite impressive. I think it's difficult to disagree with that. And then doing a phase I healthy and a phase I -B patients to kind of tie it all together and say, okay, this looks like dupilumab in people too. Now let's go and run a few large phase II and phase III studies to evaluate the full extent of the efficacy and the safety. I think that's how I like to think about it.
Does it have to look exactly like dupi because it would have a way of dosing advantage, right, an oral advantage? Sometimes when it's an oral, the bar doesn't necessarily have to be that high.
Yeah, and you know the only reason why we say that we believe based on the biology of what we've seen, I think it's widely accepted that I think if you're, I've heard that if you're 30% less active than dupi and you're an oral safe drug, you're going to be wildly successful. That's probably true, but I'm not going to set a bar that is totally artificial. I mean, where is 30% coming from? I have no idea. All I know is that based on our preclinical data, I think it's going to look like it. It can look slightly better, slightly worse, and that's why we're going to run the studies.
Okay, and then can you talk just theoretically about whether you think there's a real difference between STAT6 degradation versus STAT6 inhibition?
Great question. So what is the goal of blocking STAT6, right? The goal of blocking STAT6 is to block the translation of the signal from the receptor into the nucleus. If you have a small molecule inhibitor that can stop the translation of the STAT6 signal from the receptor to the nucleus, you should be able to do it whether you're inhibiting the protein or you're degrading the protein. Now, in our hands, in order to block this signal completely, you need to remove the protein, right, 90% plus. We can do it with the, at least based on our preclinical data, if you look at our data in preclinical species with relatively low doses in dogs and in monkeys, we haven't shared that data, but it's quite similar.
With a dose around 1 mg per kg, we can get between 1 mg and 3 mg, we can get to 90% + degradation with a single daily oral dose. The reason why we can do that is because we have a catalytic degrader that degrades the protein very quickly in the first few hours. Then we do not need to have the drug hang around for much longer because it takes 12-24 hours for the protein to come back. We can dose the next day and we can degrade whatever is left. That is why we get to this 90%+ steady state. With a small molecule inhibitor, in order to block the translation of the signal completely, you need to have an exposure of your drug that is superior to the expression of the protein 24/7.
That is extremely difficult to have a PK and a safety profile that will allow you to have an exposure that is above the target expression in every cell, in every tissue. We have not been able, we have done quite a bit of work with small molecule inhibitors in our own labs, and we are not able to generate that same signature with once-a-day oral drug.
Okay, so one of the scenarios, obviously, is you see the data that's convincing to you that this is a real drug, it's got good activity, good chance of having similar efficacy to dupi. In the scenario where you don't see a trend or the numbers are not in line with what you would like to see, then what? Do you continue to look at different molecules? Do you think about different dosing? What would be the next step?
That scenario is not considered in my mind. I will say that this is a chemistry problem, right? Is the molecule performing the way it's supposed to perform, which means is the PK allow you for degrading the target well and effectively? If you're not able to do that, obviously, because we've done it so well preclinically, I would say that it's probably a molecule problem. We believe at Kymera, across the whole pipeline, that we're not a once and done on each program. We have multiple molecules. We have next generation molecules. Should that unlikely event ever happen, we will make sure that we have other tools in our toolbox to deliver on the promise here.
Okay, and then the flip side of it, which is if you do see good data and you move this indication forward, does it open up other indications for you?
Yeah, I mean, we're setting up the development program to develop this drug in all the indications which dupilumab has been approved in, which is seven, almost eight. This initial phase II-B studies in AD and asthma will allow us to then go into multiple phase III studies in parallel because we can use the AD phase III dose to go into other derm indication and the phase III respiratory dose to go into other respiratory indications, asthma dose to go into other respiratory indications. At that time will be more of a capabilities and capital question, and I don't think it will be a scientific question. We're building a team to execute on a pretty aggressive, I would say probably one of the most aggressive development plans I've seen. I think we're already paid.
We're already paid with our runway, the two large phase II-B studies. Actually now with the extended runway, we're going to go well beyond those. It will be an interesting time for phase II- B studies to kind of see where we are as a company and see what we do for phase IIIs.
Okay, and then let's just quickly talk about oncology. That's also a focus for the company. You've talked about searching for potential partners there. Where are you in that process and when do you think is the right time?
Yeah, yeah, I would say that, yeah, oncology has been a focus of the company in the past few years. We made a decision a couple of years ago now to really focus, at least internally, actually much earlier than that, but externally we've made a decision to focus only in primarily in immunology. We've had some assets in the clinic with actually some really interesting early data. And partnering those assets is one possibility. I think it's hard for me to say when and how. I think when it will happen, if and when it will happen, we'll share it.
It's not a near-term necessity?
It's not a necessity, obviously, but it will be a great thing for patients that they can benefit from drugs that have clinical activity.
Okay, and then just remind us your current cash position and how far that takes you.
Yeah, so we have $775 million as of end of Q1. That will take us into the first half of 2028, so roughly about three years. As I said earlier, this is going to be well beyond many data readouts, including the phase II- B on KT-621.
Okay, perfect. We'll be looking out for the data next month and we'll talk to you then.
Excellent.
We're out of time for today. Thanks everyone for joining us, both live here and on the webcast. We'll talk.