A different part of the protein, specifically NBD1, and I'm sure we'll get more into NBD1 and what its role in the biology is and how this is unique and different. Our goal really is to disrupt, in a positive way, the CF landscape. We think we have an opportunity to transform the treatment of patients and provide new options, potentially more efficacious options, with a goal of getting as many patients to normal CFTR function or wild-type levels of CFTR function as possible. We know today that about two-thirds of patients who are on the standard of care do not get to normal CFTR function. So that's where the unmet need is derived from. And we think because of NBD1 and our approach, we can drive more of those patients to normal CFTR function. That's ultimately the goal. You may not know the—I'll talk a little about the history real quick because I think it's an important part of the story, because we do often get asked, how did we crack that tough target of NBD1? The company spun out of Sanofi back in 2019, but the science goes all the way back to Genzyme. So the history behind our scientific programs now is over 15 years in the making with a heavy degree of investment and perseverance against this very challenging target. And we wouldn't be where we are today without that 10 years prior to Sionna forming, being able to leverage the investment that was made between Genzyme and Sanofi. And we're now at this point where NBD1 was once considered undruggable. And we now are in the clinic with multiple programs and really on the cusp of refuting that undruggable label that has existed for many years with NBD1. So very unique opportunity. You probably know massive commercial opportunity, right? $11 billion market today that is dominated by one player in Vertex. So we give Vertex a lot of credit for what they've done. They've really provided tremendous benefits to patients with the medicines that they have developed. But as we said, we think there's room for more, and more options for patients is only a good thing. And if we can deliver even more efficacious options, that much better. So we'll talk more about that. And then just in terms of milestones and where we sit today, so as Yatin said, we completed our IPO in February. So we've been a public company now for about nine months. We continue to execute. We just launched our phase II- A proof- of- concept study with one of our NBD1 stabilizers, 719, which we'll get into that design and the difference between our NBD1 stabilizers. That is ongoing, a phase II-A proof- of- concept study to show the proof of biology, proof of mechanism of NBD1 that is differentiated but also synergistic with the components of Trikafta. And at the same time that we're running that proof- of- concept study, we're doing a healthy volunteer dual combination study of our 451 NBD1 stabilizer in combination with two different complementary mechanisms. One is SION- 2222, and one is SION- 109. So two different dual combination options. Our prioritized path that what we think about is ultimately best for patients and that we want to commercialize is this dual combination to select a double, two compounds coming together that have the potential to drive more patients to normal CFTR function. As you probably know, the standard of care is a triple combination. So we have a differentiated approach in that way. So that's our two ongoing studies. Both readouts are expected in mid-2026. So very important next six to eight months for Sionna to execute on both of those trials and then to have that data in hand. That will determine the next strategy for us as we move forward. We can talk more about selection and what we will be advancing once we have that data in hand. But hopefully that gives you a good summary of where Sionna is today. Very good. Very helpful. So what makes it a unique target and why nobody has been able to crack it? What happens when you stabilize this particular protein domain to their CFTR? Yeah, let's talk about the biology of NBD1. Why is it so important? And so what we know is that NBD1 is not a new target, right? This has been studied for a long time. The biology is very clear, but as I said, it's been considered undruggable for a period of time really because of the very challenging chemistry, very shallow binding pockets that exist around NBD1. And that's really why nobody has been able to crack it. And it goes back to the history that I mentioned before, 15 years, right? It took between Genzyme, Sanofi, and Sionna to get to where we are today, given how challenging this target is. But why is NBD1 important, right? So what we know is that the number one genetic mutation that creates or causes CF is called F508 del. You probably know this. Approximately 90% of patients have a form of the F508 del mutation. That mutation resides within the NBD1 region of the protein. So there are different regions or domains of the CFTR protein, NBD1 being one of those. That mutation resides within NBD1. What the mutation does is it causes NBD1 to irreversibly unfold at body temperature. So it's creating this instability in the protein, crippling the folding, its ability to traffic to the cell surface, and then the overall functionality. And so what you know today about the standard of care, Trikafta, is it's correcting different parts of the protein, namely ICL4, TMD1, and TMD2. Three different parts of the protein are being corrected. None of the aspects of Trikafta are directly stabilizing NBD1. So you still have this instability in NBD1. And so therefore, there's a partial correction of the protein. And what we know from our preclinical data is that by stabilizing and correcting NBD1, there is a differential outcome that you can have on the correction of the NBD1 protein itself. And what we see in our CFHBE assay, which we'll get into, I'm sure, in a minute, is that by just correcting or stabilizing NBD1 on its own, at Emax levels of concentrations, you can get to a similar level of efficacy as Trikafta. So the single agent of NBD1, nearly equivalent to the triple combination of Trikafta. Now, our goal is not to get to equivalency. Our goal is to drive superiority above Trikafta. We think there's the potential to do that because of NBD1, but we need one other mechanism to combine with NBD1 in that dual combination that I mentioned before. And in our preclinical data, if we have that double combination, we have the potential to drive all the way up to wild-type levels of CFTR function. And I know one of your questions is, why do you need that second compound? What is the value of that second compound if NBD1 is creating such a level of stabilization of the protein? That second compound for us is either going to be an ICL4 corrector or a TMD1 corrector. And those correctors, either one of those combines nicely and synergistically with NBD1. And what they're doing is really correcting the domain-to-domain assembly defects that exist. So NBD1 can correct a lot of the folding and the issues that you're seeing with that mutation. But to really fully normalize the protein, you need one other corrector to help you stabilize that domain-to-domain assembly. Got it. That's very helpful on the biology. But how have you tested this hypothesis at preclinical level? You touched on the assay, CFHBE assay. What is that assay? What is unique about that assay? How are you confident that your assay is the correct one? Yeah, so many of you may know about the CFHBE assay. This is the gold standard in vitro assay in CF that has been demonstrated to be highly clinically predictive in vitro to in vivo. And so we have a very similar assay that Vertex runs. And this was an assay that was created by academics and has been honed by industry. Vertex, ourselves, run this assay. There's a protocol on how you run it. It does take discipline and experience in terms of how to run it. But we have a high degree of confidence in our assay, just as Vertex would have in theirs. And the reason we say that is there's a lot of public information and literature out there around the assay. And even Vertex has published a lot of information on how they run the assay. We compare our assumptions and how we run the assay to how Vertex does. It's very, very similar. You can never say 100% because you don't know everything that's behind the four walls of any company. But everything that's in the public domain, we have a high degree of confidence that we run the assay very, very similar. And the proof is really in the pudding, right? What we have justified or shown in our assay is that we've synthesized the Vertex compounds in our lab. We then run them through our assay. And when we compare our assay results to the published clinical results of the Vertex compounds, they match. We've done the same with the ABBV compounds that we've in-licensed. We've also done it with compounds that have failed and would have predicted failure. So we've done it not only with successful clinical results of compounds that have been successful in the clinics, in the clinic, but we've also done it with ones that have failed and would have predicted both the successes and the failures. So we have a lot of confidence. And one of the secret, not secret, but one of the, we think, the most powerful parts of the assay is the presence of human serum, right? So this is an in vitro assay. But to more closely replicate the in vivo experience, we add human serum 20% by volume to improve that prediction. And that is the same assumption that Vertex does. That's public at this stage. And the last thing that gives us a lot of confidence, again, is that level of time and experience of our team. Our team has been running this assay for 15 years. I'd put them up there with anybody in terms of their expertise and experience with this assay. And so it is a very important part of our story, right? The predictability of that assay and what we think the potential of our programs are. And as we run NBD1, as I said, through that assay, as both a single agent and in various combinations, this is where we have the ability to do something very different and unique for CF. Got it. So let's go through the assets, right? So for NBD1, you have two assets, 719 and 451. Can you just talk briefly about the unique features of these two assets? Obviously, you have two strategies. One is an add-on, one is a dual combo. Why you are picking 719 for add-on? Yeah. And Charlotte can jump in on this too. So as you look back, we delivered the phase I results for both 719 and 451 earlier in the summer, I think the June time frame. And we were very pleased with the results from the phase I. Both compounds were generally safe and well tolerated. There was really no separation from a tolerability perspective of one compound versus the other. And both compounds exceeded the target exposure that we had set ahead of the phase one that demonstrated that both of these compounds could show clinically meaningful benefit above the standard of care. And we defined that clinically meaningful benefit in two different ways. So one is if we added either one of these NBD1 stabilizers on top of the standard of care. So we add NBD1 to the standard of care. It's mechanistically different. It's synergistic with those components. And in both cases, at every dose we tested, both compounds exceeded that target as an add-on. So that gave us a lot of confidence on sort of one approach that we could take. But as we said, the higher bar and the one that we are really going after is this dual combination that could drive clinically meaningful benefit above the standard of care. And for both compounds, at several doses, we were exceeding that target exposure required to drive that dual combination. So we really had this unique opportunity of two compounds that were delivering the profile that we wanted. And so what we did then was we initially had always thought, well, we'll just pick the best compound and we'll move that compound forward. But what we really realized was there were some unique differences between 719 and 451 that we might be able to leverage in a way that would maximize the clinical development strategy. And what that was, as Yatin referred to, is we're going to take 719 forward as the add-on to standard of care NBD1 stabilizer. And we'll talk more about that study. And then 451 is going to become the anchor to our dual combination program. The reason we did that is, again, when we looked at the unique differences of 719 to 451, 719 is a little bit more potent than 451. And where that really showed up and manifested itself was at the lower doses that we tested. So if you look at the lowest dose we tested of 719 and you compare the lowest dose that we tested with 451, 719 got higher levels of exposure than 451 at those lower doses. So what we want to do from an add-on strategy, the goal was always to add a low dose of NBD1 on top of Trikafta because you're adding a fourth compound to a triple combination that already has a tolerability profile. So we didn't want to disrupt that in any way by adding the fourth compound. So we needed a low dose compound, but yet that could drive the efficacy we were seeking to drive that clinically meaningful benefit. And 719 sort of won that bake-off, if you will, between the two different compounds. The converse was the dual combination, we actually need more exposure from NBD1 when we're only combining it with one other agent. And so in this case, 451 achieved higher levels of exposure at higher doses. And so that profile was differentiated and really became the best dual combination option for us. So again, we had this unique opportunity where we could have picked either one of these compounds to go in either direction. And at the end of the day, what we tried to do is really leverage the unique profile that would put us in the best position to execute both the add-on study and the proprietary dual combination. Got it. So let's take the add-on strategy first. So the precision study that you are running, what is that study? What do you hope to achieve? I think you have established certain thresholds. How do you come up with those thresholds? Yeah, Charlotte, you want to talk about the study? Yeah, so it's really meant to be an efficient, as Mike said, proof- of- concept, proof of biology study. We're really leveraging the fact that a fairly low dose of, in this case, 719 can really drive predicted substantial benefit, clinically meaningful benefit when added to the standard of care. So we're going to enroll patients, and that study is in active screening. It's open. You've heard that. We're going to enroll patients who are stable on physician-prescribed Trikafta. So that's background therapy. They stay on their Trikafta for the entire study. Nothing changes with the Trikafta, standard labeled dose of Trikafta. And then what they'll do is we'll have a two-way crossover study, which actually allows us to be super efficient and do this in less than 20 patients. They'll get two periods of two weeks of either 719 added to their Trikafta and two weeks of placebo. Now, it'll be randomized. They won't know which one comes first. But every patient will get both of those periods. And the outcome, so the primary endpoints are safety and tolerability, but also the primary activity endpoint is sweat chloride, the clinical biomarker of CFTR function. And the properties of sweat chloride are what really allow us to do this so efficiently and to be powered for at least that 10 mmol per liter change in sweat chloride, which we know is clinically meaningful. So that's the power of the study, which means that that's sort of the floor of that outcome. And so the outcome will be in every two-week period, the change from baseline in sweat chloride at the end of the two-week period on 719 plus Trikafta versus just on Trikafta alone. Do you want to talk about the 10 mmol? Yeah. Where does that come from? Yeah, so that's actually been a threshold in the community for decades. When you look back, even before as the approved modulators were in their early days, epidemiologically, if you look at ranges of this clinical spectrum of people with CF, those F508 del, homozygous, and minimal function patients all have quite severe CF. All of CF is severe, but they're on the severe end of it. But if you look at some of the gradations, 10 mmol per liter of sweat chloride just naturally kind of was a differentiator in terms of clinical severity. And then that really was the kind of bar that was set for optimizing even the approved modulators. And you look at the first modulators that worked in the F508 del population, Orkambi and Symdeko, those actually both had, from a non-modulator baseline, something around a 10 mmol per liter change in sweat chloride, and then associated with that around at least a three percentage point of FEV1. So that's become the bar based on a number of things. Got it. And we did follow up, Yatin. Charlotte has that historical reference of where that came from. But we did go out and do a survey with KOLs and ask the question, is that still the bar? Is that still what you consider? If you have a standard of care that delivers a certain level of efficacy today, how much above that would be meaningful? And that 10 mmol of sweat chloride and about three points of FEV1 consistently comes back as that's meaningful. That would make a difference. That would get us excited about that. Obviously, anything beyond that, even more so. But that's how we set that minimum bar, was both on the historical precedents that Charlotte talked about and then getting that market research, right, with KOLs. Has anything changed? And it has always been consistent at that 10 mmol of sweat chloride and about three points of FEV1. Could you also maybe put in perspective what we see with Alyftrek? I was chatting with Elena last week. I think she pointed out certain nuances about the patient population. It's not that Alyftrek is showing you 10. It's less than that, depending on the population. If you can put that in perspective. Yeah, yeah. So we know just to we know that the changes in that there were two major phase III studies with Alyftrek versus Trikafta. So very, very well-powered head-to-head. And in the F508 del homozygous population, the change in sweat chloride with Alyftrek was about a three mmol per liter. And then in the what are called the minimal function, F508 del and either a null or a minimal function mutation on the other, the change was about a seven or an eight mmol per liter. And so in that case, we actually were not surprised when those trials read out to see that there was no change in FEV1. And so as you know, that that was approved, Alyftrek was approved based on non-inferiority of FEV1. So if you look back over the history of CFTR modulators, that something below 10, not only is it sort of, is it clinically meaningful? Maybe some people may consider it helpful, but it has been very noisy and has not always translated reliably into FEV1. In our study, but to your also following question, our study with the phase II-A that Charlotte described, the precision CF is going to be in homozygous. Yeah. And if you compare to what she said, that's the 2.8 sweat chloride that was shown in Alyftrek was in homozygous patients. So if you want to compare across genotypes, that's how you do it. Okay. What about FEV1? How long it takes for these types of medications to show the FEV1 benefit? I know that's not the endpoint for this study. That's not the bar. But just curious to understand how you're thinking about the time it takes to show that improvement. Yeah. So really, if you step back, our goal ultimately will be to show an improvement in FEV1. And this particular study, which is a two-week study, which is not long enough to plateau FEV1, our goal is to show that if the kinds of sweat chloride changes or CFTR function changes are substantial enough that we will predict that that will then translate in later longer studies into FEV1. So that's our goal really from the beginning. You need historically somewhere at least around four weeks to see a plateau in FEV1. And then you also importantly need power. So it's not just duration, but it's also the numbers. So these data are coming when? Mid- 2026. Mid- 2026. Both studies, yep. So I think the way we look at it is that if these data, if you meet these thresholds, it validates the biology, right? It validates your assay. So two things that get validated. What else? And how should it read through to their dual combo approach? Yeah. So you want to talk about? Yes. So we really see this as having three major functions. One is, as you said, proving the NBD1 hypothesis, which has been out there for decades. Two, really allowing us to correlate back our own CFHBE assay with clinical predictions. And then importantly, it also we expect to show that patients stable on the standard of care, that there's still plenty of room to improve CFTR function. So we think all of those things are going to be important for later stage studies. Got it. And then that translation to the dual combo, right, Yatin? So if you think about that proof- of- concept study is really meant to be that proof of biology, proof- of- concept. And our preferred path and prioritized path is the dual combo. But that first study, it is a proof of mechanism. It's going to demonstrate, as Charlotte said, the biology of NBD1 and the translation of the assay, which is then also going to help validate the translation of the dual. So even though it's 719, it's an NBD1 proof- of- concept, right? It's not so much the compound or the compound proof- of- concept. It is the biology. And that will give us, again, that confidence in that how it translates in the add-on will help us demonstrate even further the strength and the demonstration of that translation in the dual combination path. Got it. And then for the dual, number one, when is that data coming? And then you have a TMD1 and ICL4. Is one versus the other better with NBD1 biology doing now? So that's dual combination timing is the same. It's mid-20 26. So that we're expecting the data around the same time as the add-on and the dual should be reading out at the same time. And you're right, the two different compounds, so SION- 2222, that's a TMD1 corrector that we licensed from AbbVie. And then ICL4, SION- 109 is our ICL4 corrector that is a Sionna proprietary compound. Mechanistically or biologically, either one of them combines nicely with NBD1. There's no difference in the biology of why you would pick one versus the other. The selection that we will make is going to be based on the compound performance. How does the combination work, right? So it's really going to come down to which one of 2222 or 109 performs better in combination with NBD1. So we're sort of agnostic to mechanism, right? ICL4 versus TMD1. It's really going to be about the PK and the exposure that we get in the dual combination work to translate back into our assay. And then how safe and well tolerated are those in combination with NBD1? And that's what's going to help us make the selection. And so the dual combo study still is in healthy volunteers. So just from a biology and preclinical, the precision is more important, at least. So precision is the first CF patient data, right? For all the things that Charlotte said, those three or four different benefits of that study. One other one that we also have is that will help us enroll in the later stage study. Because now you actually have CF patient-level data. So that's a fourth kind of benefit of that study. The dual combination is in healthy volunteers because we want to get that combination right, right? We want to test different doses. We want to see how they play together. And it's just easier in healthy volunteers to do that to optimize your dose, which will then lead us into the next stage of development for the dual, which will be the dose ranging in CF patients, right? That will help us select the dual combination. And then the next stage will move into dose ranging. And I would just say PK is translated very nicely from healthy volunteers to PK with CF. Got it. Elena, how is the financial health of the company? Yeah, we're in a strong position. We ended Q3 with $325 million in cash, which provides us cash runway into 2028. So meaningfully beyond these milestones we just talked about reading out mid next year. Well, very good. Thank you so much. Thanks, Yatin. Thank you. Yeah, great to see you. Thanks for having us. Thank you. Thank you.