Morning everyone. Thank you for attending Jefferies Global Healthcare Conference. My name is Kelly Shi, a Senior Biotech Analyst here. We are very pleased to have Dr. Nello Mainolfi, Chief Executive Officer, and Dr. Jared Gollob, Chief Medical Officer from Kymera Therapeutics for this fireside chat session. Welcome both.
Thank you. Thanks for having us.
Before we dive into individual clinical program, could you discuss Kymera's technology platform and how it differ from your peers on targeted protein degradation enabling Kymera to achieve maybe others might not be.
Thank you. Thanks for the question. We founded Kymera about nine years ago with the goal of using targeted protein degradation, which is a technology that uses small molecules to remove disease-causing protein. We wanted to use this technology to go after protein targets that have never been drugged before. Drugged well. What we evolved along the way is, I think, the unique ability to marry the power of the technology with the right target to develop really unique profiles. You know, in the past, let's say five years or so where we've dedicated our efforts mostly or only in immunology, we've been able to demonstrate both preclinically and as well as early clinically that we can develop oral drugs that can block pathways as effectively as biologics and hopefully for the first time develop orals with a biologics-like profile.
That has been the underlying investment thesis at Kymera and that has then evolved into building a pipeline of oral drugs that I believe is one of, if not the best, oral immunology pipelines in industry, with going after again targets that have not been drugged or drugged well before. You can think about STAT6, for example. That is an undruggable transcription factor in a highly validated pathway like the IL-4/IL-13 that has never, again as I said, never been drugged before, with strong human genetics data. IRAK4, again, another poorly drugged target in the IL-1 TLR pathway. IRF5, another drugged transcription factor in the, let's say, TLR cytokine pathways. These are all targets that again needed the right unlocking technology, and we've been able to do that at Kymera. The other important aspect of the company is the capabilities that we built along the way.
Our ability again to go after these really difficult to drug targets comes from large investments we made in identifying small molecules that can bind selectively and specifically to these difficult to drug proteins. Our structural biology capabilities, chemistry capabilities, screening capabilities allowed us to again develop drugs like KT-621 that now we have clinical validation of the unique specificity that translates into this unique safety profile.
Fantastic. You have a strong focus in inflammatory and immunology diseases and continue to expand the pipeline. We are curious, when you screen and select each target for each program, what are the strategic thinking behind?
Yeah, so as I was trying to say earlier, we have kind of four key pillars that we, parameters I should say, that we use to select targets and I will say that those have not changed materially over the past nine years. One has to be, again, a target that has not been drugged or drugged well before, has to be in a pathway that has been clinically validated. Again, we can use STAT6 and the IL-4/IL-13 pathway, a target that has strong human genetics. Ideally, we would like to see both loss of function, again, of function, genetics on the target.
We know what happens if the target is activated and what is the safety if the target is removed and then the ability upon us developing a drug for that target to address large patient populations, which is something that we believe is critical in today's evolving landscape of how drugs are prescribed, reimbursed in the U.S. or all around the world.
Great. Maybe dig a little bit deeper into STAT6 program. The healthy volunteer data released on Monday clearly exceeded investor expectations. Congrats on the big milestone to start. Could you walk us through the development timeline for this program and at a highlight level, why you view this program as one of the most important programs in the I&I space?
Yeah, thank you. At the high level, maybe just to do a very, very quick recap, I mean as I mentioned, I think there are very, very few targets across all, I would say across all disease areas where you have a one to one relationship between a receptor and a transcription factor. The ability to use all the validation of the drug that targets the receptor, in this case DUPIXENT, dupilumab, which is one of the most successful drugs in history. You know the diseases which it works in, you know how it works, you know that it's actually one of the few, if not, I would not say probably the only, but one of the few drugs that is used for immuno- inflammatory diseases that is not immune suppressant, it's not considered immune suppressant.
You have an amazing drug that works through targeting the receptor and now you have a transcription factor that is selective for that receptor. If you're able to drug that transcription factor, you should be able to replicate what has been done with the receptor blockade. That's the thesis that we've had from the beginning. Why is it one of the most important program, at least we believe, is because again, for all the reasons I've said, you know, DUPIXENT is going to be probably a $25 billion drug in the next 3-5 years, has a potential patient population of more than 100 million patients. At least this pathway in the seven major market, it's really only been those to roughly a million patients. We have a huge opportunity not only to enter that market, but to actually build that market.
If we just think about atopic derm, which is where 80% of the revenues from DUPIXENT come from, that is a very immature market. There is really only one really safe and effective drug that dominates the market. There is DUPIXENT, there are some other biologics that are coming to market and then there is an oral drug with a challenging safety profile. I would say AD is where probably psoriasis was 15 years ago or so. We need to build that market and a safe and effective oral drug is going to transform that space. That's really what we're talking about here. That goes beyond AD, asthma, COPD and others.
Great. We would like to take a closer look for this healthy volunteer data. Before the data release we were actually trying to figure out how to interpret when we got a data set and how much of a read through to patient trial given not too much prior studies we can actually leverage. Maybe Nello, at this moment from the whole data sets, what data point would you highlight the most meaningful and exciting? Also, from this beating exploitation data set, would you still say there's limited resource to patient trial? We would like to hear your thoughts.
Yeah, maybe I'll address the first part and Jared can address the second part. The first part is we've always said for the past nine months that the most critical data for the study had to be degradation and safety. Because again, we built the package preclinically that if you degrade the target, you can have a dupi-like effect. If you degrade it 90%+ the real question was can we degrade it? We had high confidence of being able to degrade targets. We've done it over and over again. Nobody had drugged STAT6 in humans. We had confidence, but obviously the question what is the safety profile going to be? I think what really surpassed our expectations are two things. First, we were able to degrade 90% or more at all doses. Besides one, the only one that was less than 90% was the 1.5 mg dose.
I would say that that dose was selected at the end of the study where we decided we need to figure out when what is the dose that degrades less than 90%. We had to go all the way down to 1.5. We were not planning to actually even dose that low, but the drug outperformed our potency expectations in humans. We were able to fully degrade the target in blood and skin. Remember, that is a very, very high bar to being able to degrade in blood and skin. We were able to do it completely at doses of 50 mg and above, where most subjects were below the lower limit of quantitation. That also exceeded our expectation. The last thing was safety.
I personally have been doing this in small molecule drug development my whole career and I've never seen a safety profile that we've seen in this healthy volunteer study where the lowest dose 1.5 mg and the highest dose 200 mg or if you look at study 800 mg, there was no difference in safety. They were all again, placebo-like safety. That was a compelling data set that actually is pretty much in line with what we had seen preclinically. Obviously you want to see that translating in humans, maybe. Jared, do you want to speak to how any of these will translate into read through?
Yeah, I think in terms of read through, I think there we think about how will what we saw with regard to degradation of the target and impact on the pathway ultimately de-risk or affect the probability of success of seeing clinical proof of concept in phase I-B. And if you hearken back to our preclinical data in our house dust mite asthma model, for example, where we showed that 90% degradation of STAT6 gave dupi-like activity, activity actually comparable or even superior to dupi, you know, a full saturating dose of dupi in that model system. That's why we set that bar at 90% going into the phase one study.
The fact that now we've exceeded that bar, showing complete degradation, where we have 95% or greater reduction with majority of subjects going below the lower limit of quantification at doses of 50 mg or greater in the MADs study, I think gives us a lot of confidence. In addition to the fact that we could see effects that were either dupi-like or even superior to dupi on TARC and on Eotaxin-3, which is telling us that profound degradation leads to substantial pathway blockade that is on a par with the sort of pathway blockade that you see with dupi IL-4/IL-13 pathway blockade.
We think that now that heightens, we believe, the probability of success in phase I-B of being able to show hopefully in phase I-B the same degree of STAT6 degradation in blood and now inactive skin lesions in these patients to be able to show a dupi-like effect on Th2 biomarkers in blood and in active skin lesions and to also be able to start to show some impact on clinical endpoints, realizing that that I-B is a four- week 28- day study. We know that even with dupi in randomized placebo controlled studies at 28 days you can see significant impact on biomarkers like TARC in the blood, on skin biomarkers and on clinical endpoints. What we want to see in phase I-B is sort of internal consistency. We want to see that STAT6 degradation comparable to what we saw in healthies.
We want to see evidence of pathway blockade with even more ability to look at that Th2 pathway blockade by looking at multiple Th2 biomarkers in phase I-B and then start to look at clinical endpoints. Even though this is a single arm non placebo controlled study, we can look for internal consistency between degradation, biomarker effect and clinical endpoints. I think all of that will hopefully provide a substantial proof of concept in that study. That would then be the sort of read through that we expect.
Fantastic. Maybe a follow up question here is for phase I-B, we probably can expect a similar extent on protein degradation for STAT6, but for biomarkers where we should pay special attention and also on safety, healthy volunteer data seems like very clean. After we extended the treatment, anything on your mind on safety profile?
As Jared just said, I think that the great opportunity in patients is that at least some of these biomarkers, like TARC for example, is elevated at baseline. Actually, more importantly, the pathway IL-4/IL-13, given that AD is a Th2 disease, will be driving the majority of the TARC that we see. That is why in the dupilumab study you see between 70% and 80% inhibition of TARC even around four weeks. That is because the TARC is generated by the pathway and with a strong drug like dupilumab you are able to block it. That will be a good bar to set for us. Those are kind of numbers we are going to be looking at.
I think what has been shown also is that there is a very well established signature in the skin lesions, as Jared said, of AD patients, of a set of genes that are modulated by IL-4 and IL-13. Being able to show that having a signature that is robust in the skin lesions of AD patients will be important on safety. As we've said, in preclinical study, we actually have not seen any adverse events in the clinic, again undifferentiated from placebo. We continue to expect a very good safety profile even when we go from two weeks to four weeks.
Great. It's still early days. But curious as a potential oral option next to dupi in AD, how would you position the STAT6 program and how do you integrate the thoughts into the future phase II-B, phase III trial design? For example, would you actually include patients who had a dupi experience and also like basically commercially how should we think where this is actually placed among other AD options?
I think Jared should speak to the high level, maybe phase two trial, but just commercially. Again, as I said, there are no approved drugs with a good kind of risk profile, risk reward profile in terms of safety and efficacy. We believe strongly that an oral is going to transform the landscape. Our kind of right now going into assumption based on all we've seen so far is that we should be able to have a dupi-like effect. Obviously, we've done market research that says to us that you do not even have to have a dupi-like effect to be a successful commercial drug. Nonetheless, I think biology so far is telling us that, so we will continue to have that as a bar, and I think that that will be a drug that has the opportunity to transform how we think about treating patients.
I believe it will be, it should be the first in line drugs for all these Th2 diseases. I am not sure that we need to get over creative in the development to demonstrate differentiation over dupilumab, but maybe I'll let Jared comment on at least our thinking high level in the phase II-B.
Yeah, I think as Nello was saying earlier, the AD population is so large and only a very small fraction of that population is actually currently being treated with dupilumab. That our aim is not to really feel like we need to go after dupi failures of people who have progressed after dupi. There is a very large population where we could be the first therapy. When we are looking about thinking about eligibility, if you look at our current phase I-B, you know we allow patients who are dupi naive and we also do allow patients who have had prior systemic biologics including dupi, provided they have not progressed on that biologic. They cannot be refractory to it. Because again, the aim is not to try to position this drug as a drug that is going to salvage patients who have had progression on dupi.
In fact, in reality there are very few patients who do progress on dupi. I think likewise when we think about phase II-B, this will be an important dose range finding study both in AD and in asthma. We've guided that the AD study, the phase II-B AD will be later this year in Q4 and then the asthma study in Q1 of next year. The dose range finding study again will enroll patients with moderate to severe AD just as the phase I-B is enrolling those patients and will allow both biologics-naive patients and patients who have had prior biologics. Again, patients who have not progressed on dupi.
If somebody was on dupi and they came off just because they could no longer get coverage or they came off because in the rare instance where they're not tolerating it, those patients would be allowed to be on the study. Thanks.
Great. We saw another approach tackling STAT6 next to degrader. Actually, from last year we have seen a couple of deals on STAT6 inhibitors. Maybe share your thoughts with us. What are the advantages to design a degrader versus inhibitor?
Yeah, I mean there have been a few deals on inhibitors and degraders. Obviously we did not invent STAT6. Right. I think this target has been in the public domain for a while. It has been on the top list of several large companies for the past at least 10 years. We were the first to actually show you can actually drug this target selectively. Specifically, importantly, together with the already interest, I think there has been now, let us say, early for us a preclinical validation, now clinical validation. It is not surprising that if you have a drug that could be a mega blockbuster, there is going to be an effect of the industry trying to follow and trying to find other assets. Given that our strategy has been clear from the beginning that we are not partnering this program, to now answer your question about inhibitors versus degraders.
What we've learned so far is that you need to degrade the target really robustly, again as we've said preclinically, 90%+ , to see a pathway blockade that can match dupilumab's pathway blockade. If you talk to the dupilumab's team, they will tell you that you probably need to hit the target for sure, more than 90%. I'm talking about the receptor now to see the effect that they see in the clinic. Our view is with a catalytic degrader like KT-621 that does not require high exposures to be occupying the target 24/7, but it only requires exposure to degrade the target and then relies on the slow resynthesis rate of STAT6.
We can do that as we show now clinically, very efficiently with low doses as a once a day oral drug, I think, and that's based on the data we've generated. I believe it's almost impossible with the occupancy based modality like small molecule inhibitor to have the exposures that are going to block this pathway as effectively as a degrader or as a biologic. I think you can block STAT6 with a small molecule inhibitor, but I believe you're not going to be nowhere near the efficacy that you've seen with dupi or hopefully with our degrader once we're in patients.
Great. We would love to learn the nuance of differences targeting STAT6 versus targeting IL-4 and IL-13 given that the commercial drug mostly builds on the IL-4 and IL-13 pathway. In theory, what kind of implication on efficacy and safety from targeting STAT6 versus other drugs?
Yeah, so first, I mean the reason why we keep talking about dupilumab as the bar for us is because dupilumab is the only drug in this pathway that blocks IL-4/IL-13. The important thing about blocking IL-4/IL-13, you actually block all Th2 inflammation. If you block IL-13 only, you will block only part of Th2 inflammation. That's why dupilumab is the only drug that is approved in all these indications, unlike let's say the IL-13 families, and STAT6 degradation is the only approach that can phenocopy IL-4/IL-13 blockade. The reason why we believe, based on all the data we've generated so far, both preclinical and clinical, that the safety and efficacy should be the same is because if you activate the IL-4 receptor, you recruit STAT6 to the receptor to then propagate the signal intracellularly.
There is no data that we've been able to uncover that shows that IL-4/ IL-13 signal through any other transcription factor. Now, I'm not saying it's impossible because science is obviously very complex, but we haven't been able to see it. In all the studies that we've run so far, including the clinical data, it confirms our hypothesis. That's why we believe, and obviously we want to continue to generate data to substantiate these kind of statements.
Okay. We have spent a good amount of time on STAT6 and a very insightful discussion maybe at IRAK4. We also have two data readouts from phase II in HS and AD next year and the trials running by our partner Sanofi maybe tell us where we are and how should we set our expectation .
Yeah, so I mean as many of you know, IRAK4 was the first program that we actually started at Kymera many years ago now. 474 was our first development candidate. So we at Kymera ran an excellent phase one study in healthy volunteers with really robust degradation and also impact on biomarkers. Then we also ran a phase I, let's call it B study in HS and AD with some really promising early data. The program has transitioned to Sanofi and they've been running initially a phase II study and then later announced the desire to expand into a II-B study. Obviously we're in contact with them. As far as the latest, we are still on track with what is being shared externally and the expectations around those studies is being able to show an activity that is differentiated from placebo.
We don't have necessarily a target there because also again in those indications I just talked about, AD and HS, there are no small molecule oral drugs with an efficacy and safety profile that is balanced. I think there are still opportunities there.
Great. You recently announced a new I&I program in the making. Target name IRF5. How much do we know on biology and what does the preclinical information tell you which indications we should prioritize?
Yeah, maybe. Jared, do you want to take this one?
Yeah. I mean we know quite a bit about the biology and the genetics of IRF5. It's a key transcription factor that's very important to mediating signaling through many different Toll-like receptors, especially Toll-like receptors that are involved in driving interferon production, type I interferon production, pro inflammatory cytokine production and autoantibody production. You know, it signals not just through Toll-like receptors, but through other receptors through which various so called DAMPs and PAMPs also are ligands. This is really a very important protein within the innate immune response pathway that also even dovetails into adaptive immune responses.
There's a lot of strong genetic validation for the role of this transcription factor, this master regulator of innate immunity in diseases like lupus, for example, and other interferonopathies, including Sjögren's syndrome, systemic sclerosis and others, and even genetic validation for its role in diseases like inflammatory bowel disease as well as rheumatoid arthritis. There's been a lot of interest in this particular target. It's just been very difficult to drug, as you can imagine, because it's a transcription factor. We now have a very potent selective degrader of IRF5. We've shown, I think, very compelling data in various preclinical models just recently in a company presentation showing that we're quite active in models of lupus as well as in models of rheumatoid arthritis.
We're very excited about the potential of a degrader in being able to go after this target and provide real opportunities for addressing unmet need in these diseases like lupus, other interferonopathies, and as I mentioned, other diseases like RA and IBD.
Maybe timing on IND.
Yeah, so I think we've said we'll be in the clinic early next year.
Okay, great. Lastly, would you like to reiterate the data catalyst and milestones in the next 12 months from Kymera?
Yeah. Maybe with that, as of the last Q, we've said that we have $775 million that allows us to fund all the things that we've talked about here today through the first half of 2028. We'll be able to read out several catalysts, including the phase II-B studies for KT-621 actually well before the cash run out date. The important catalysts obviously for us are the phase I-B study with KT-621 in the fourth quarter, initiating two phase of these studies, one in AD, one in asthma late this year, early next, initiating our phase I study with KT-579, IRF5 degrader, early next year with phase I data ready next year, and obviously the IRAK4 phase II data with Sanofi.
We also announced in the last quarter that we received a milestone from Sanofi on a preclinical development milestone on a full-on molecule for IRAK4. That's also an important other program within our pipeline that unfortunately we can't disclose much of, but another one to keep track of. Lots going on in the company. Likely we will share a new program next year as well. That's going to be another fascinating story, I believe.
Fantastic. I'm looking forward to it. And lastly, thanks again Nello, and Jared for great discussion.
Thank you.
Thank you, Kelly.