This is Life Sciences. Welcome to day one of our conference for 2025. We're pleased to have Sionna Therapeutics and CEO Mike Cloonan to run us through the story here. I think this is, you know, one of the more interesting stories, one of the recent IPOs in the sector, which we haven't seen many of. I think a lot of high interest, I think a lot of interesting science, and going after one of the more compelling opportunities that we've covered for many years, cystic fibrosis. Mike, looking forward to hearing the story. I'll let you take it away. Thank you, John. Appreciate it. As John said, I am Mike Cloonan, the CEO. It's a pleasure to be here with you today. Thanks for joining the presentation, and thank you, citizens, for the invite. Just to get going, we will be making forward-looking statements. Actual results may differ from those statements. I am going to just start with an acknowledgment of the Sionna team. We're very proud of the team that we've assembled. This is a great group of individuals that was brought together to revolutionize the treatment paradigm in CF, and we think we've got a very exciting opportunity ahead of us. I also want to take this opportunity to give you a little bit of the legacy and the history of Sionna. Sionna was founded in 2019 as a spinout from Sanofi, but the science goes all the way back to Genzyme. We've been working on these programs now for well over a decade. I bring that up because often we get asked the question, how has Sionna cracked this very challenging target in NBD1? We would not be where we are today without that legacy and the level of investment that was made from Genzyme to Sanofi and now to Sionna. We're very well positioned because of that history, legacy, and perseverance against what has been a very challenging target. Let's get into these four key elements of the Sionna story, and we'll get into each one of these throughout the presentation. As I've said, we are clearly focused on doing something unique and different in CF and creating additional opportunities for patients to drive and improve benefits. If you look at the four components here, we'll start with the unmet need. Despite the advancements that have been made, we all know Vertex has been very successful, and you give them a lot of credit for what they have done. Despite those advancements, the unmet need continues to be high in CF. One of the key areas that we look at in defining the unmet need is the number of patients that are getting to normal CFTR function. We'll talk more about that. Even on the standard of care today, Trikafta, only one-third of those patients are achieving normal CFTR function. That means two-thirds are not. That is the opportunity for us. We believe we have the opportunity to drive more patients to normal CFTR function because of NBD1. If we can do that, we can create real clinical meaningful benefits for patients. Also in this very large market opportunity that's $11 billion today and growing, it's a very significant commercial and business opportunity for Sionna. I've referenced NBD1, and you see it here in the second column. NBD1 is not a new target. It has been well understood. The biology is clear of what its role is in CFTR correction. For many years, it has been considered undruggable, mainly because of the very shallow binding pockets that exist around NBD1. What we believe is that NBD1 is the key to delivering more CFTR correction, driving more patients to fully normal CFTR function. We also know that none of the approved modulators directly stabilize NBD1. It is truly unique and differentiated. The third part that we'll talk about today is the predictive CF HBE assay. This is the gold standard in vitro assay in CF that has been demonstrated to be highly clinically predictive. We're very confident in our CF HBE assay and its predictive power. We use the assay in two different ways. One is we use it as a screening tool very early to identify the compounds that have the most activity in the assay. We also use it as we move it into the clinic to determine the very specific go, no-go criteria or exposure targets that we need to achieve in phase one, that the assay then or the assay implies that we need to deliver to get to meaningful clinical benefit for patients. We'll show you what that looks like. Very confident in the CF HBE assay. The last part on this slide to talk through is, as much as NBD1 is a key focus and it is the differentiated part of our story, we are also investing in complementary mechanisms that when you combine them with NBD1, this is where you have the potential to deliver more function, CFTR function for patients, get more patients to normal levels of function. You may have seen we recently did the deal with AbbVie where we in-licensed three of these complementary mechanisms into our portfolio. If we skip ahead, I did want to think a little about it and talk about NBD1. I'm going to focus on the bottom right side of this slide to talk about the biology and why NBD1 is so important. We know what causes CF. It's genetic mutations to the CFTR gene that impacts the CFTR protein. If you look at the different regions or domains, you see that bottom left maroon-colored area, that's NBD1. If you look within, you see that green circle that's labeled F508del mutation. We know the number one genetic mutation that causes CF for approximately 90% of patients is a form of F508del. That mutation resides within the NBD1 region of the CFTR protein. What the mutation does is it causes NBD1 to irreversibly unfold at body temperature. It is creating this instability in the protein that's crippling its folding, the trafficking to the cell surface, and then its overall functionality. What the triple combination of Trikafta does is it's correcting around NBD1. It is not directly stabilizing NBD1. Trikafta corrects ICL4, TMD1, and TMD2. It is partially correcting the protein. NBD1 is still unstable in that construction of Trikafta. What we believe, and we'll show you in the assay data that we have, NBD1 is so critical, and the power of NBD1 is such that if you can stabilize NBD1, it has the potential to drive nearly the equivalent level of correction as the triple combination of Trikafta. A single agent nearly equivalent to the triple combination of Trikafta. What we also know is that if you can just correct one other part of the protein in addition to NBD1, this is where you have the potential to fully normalize CFTR function, which again is our goal. I'll reflect this in our assay data coming up. From a pipeline perspective, we think of it in two dimensions. There is the NBD1 top part of the slide here where we have two different compounds that are in phase 1. The bottom half are the combination options that we would combine with NBD1 where we have four different options. Let's talk a little about 719 and 451, our two NBD1 programs that are both now finishing up the phase 1. We're very encouraged and very pleased with the interim data that we have on both of those programs. We expect to have the top line data this quarter. We are nearly completed with the phase one studies. I'll show you some of the PK and the tolerability profiles. What you're going to see for both of these compounds, they have both achieved the target product profile that we set out ahead of the phase one, which was that both of these compounds enable a dual combination that has the potential to add clinically meaningful benefit over the standard of care. That is our target profile, a double combination that could compete directly with the triple combination of Trikafta and Aleftreq. We will share that data, but very encouraging that both of these programs could be advanced, but we want to get the totality of the phase one data to determine what is the strategic path forward for these two compounds. As I said, on the bottom half, the four compounds that you see, the clinical stage assets that you have here are various options to combine with NBD1. The three star assets that you see are the AbbVie programs that we in-licensed. Both GallaCaptor and Navacaptor have phase two data. We also have our own ICL4 corrector in SION-109. When we look at the various combination options, we are going to prioritize two of these to combine with the NBD1 portfolio. We're going to prioritize GallaCaptor from AbbVie and also 109, our ICL4 corrector. They are both excellent combination assets with either of the NBD1 programs, but this will give us an opportunity to have multiple shots at combinations going forward. From a strategy perspective, you might have been able to piece this together, but it's always good to see the visual representation of what we're targeting. If you look at the bottom part of this slide, one of the ways, because of how differentiated NBD1 is, we have multiple ways to approach the market. One of the ways we could approach it is just adding NBD1 on top of the standard of care. If you flash back to the biology slide, you saw that mechanistically NBD1 is different from the components of the standard of care, but it is also synergistic with those components of the standard of care. We could just take NBD1 and layer it on top to add meaningful clinical benefits to patients. That is more of our minimum product profile. Our target product profile is what I keep referring to as the dual combo, where we would take NBD1 and add one other corrector to that, whether that is a TMD1 corrector like 2222 or an ICL4 corrector like 109. That dual, that Sionna proprietary dual combination that could drive meaningful clinical benefits over the standard of care, that is our target profile. As I mentioned, with both 719 and 451, either one of these paths are enabled based on the profile that we have seen in phase one for both compounds. We are very fortunate to have a lot of strategic flexibility in how we progress 719 and 451. Just by way of a few recent events, you probably all saw, as John said, we recently did the IPO back in February. We raised $219 million. That has provided a lot of financial flexibility for the company. We have runway into 2028 now, which helps us with the execution ahead of us. We're doing an excellent job in executing the phase one programs. As I said, we look forward to the release of the top line data later this quarter on this very novel and differentiated target of NBD1. The pipeline that we added to with the AbbVie deal was also transformational, giving us three additional shots now to do the combination studies, which is the ultimate target product profile. Lots of great progress and execution. Very proud of the team and what we've been able to do in a short period of time. Let's talk about the NBD1 programs. We've talked about the CF HBE assay, and I'm going to share a couple of slides, one for 719 and one for 451, that illustrates the power of NBD1 and the potential that we have in these dual combinations. The CF HBE assay measures chloride transport, and that's what you see on this slide on the Y axis. Chloride transport can then translate to sweat chloride and ultimately FEV1, which is the clinical endpoint in CF. What you see here is a relative view of our programs compared to the Vertex compounds. If you look at all the black circles, those are different Vertex compounds that we have synthesized and run through our assay and these other results. If you look at the top black dot, that's elexacaftor, tezacaftor, ivacaftor, that's Trikafta. It sits on the relative scale at one because that is the standard of care today. If you go just below Trikafta on that, you see the red dot that's labeled SION-719. That's the monotherapy, the single agent NBD1 by itself. You can see as a single agent nearly equivalent in the assay to the triple combination of Trikafta. It speaks to the power and potential of NBD1. Our goal is not to develop monotherapy that could be nearly equivalent. Our goal is to get to improving clinical outcomes and benefits for patients. How do we do that? If you go up the curve, you can see two different dual combination options that I've referenced before 719, the NBD1 program, combined with 2222 or combined with 109, both of those combinations have the potential to deliver wild-type levels of CFTR function, fully normal CFTR function at Emax levels of concentration. That would be an amazing outcome if we could deliver something like that for patients. We also know if you drift down the Y axis here and you get to that teal hash line that says minimum target for clinically meaningful benefit, that teal line represents our minimum target that we aimed to achieve in the phase one. What that target represents was based on our engagement with KOLs, the Cystic Fibrosis Foundation, and the community. What they told us was to drive meaningful benefit above the standard of care, we need to see at least a 10 millimole sweat chloride improvement above the standard of care and three points of FEV1. That's what that hash line represents. That's the translation in the assay of 10 millimoles of sweat chloride and three points of FEV1. You can see 20%-25% improvement over the standard of care. That was our minimum bar that we set when we went into the phase one studies, the exposure we need to achieve that would deliver that level of benefit. You are going to see that same teal hash line superimposed on the PK curves that I'll show you. Just keep that in mind as to what that represents. A similar picture for 451, our other NBD1 stabilizer. You can see monotherapy nearly equivalent in dual combinations that potentially get to wild-type levels of CFTR function. We're very fortunate we had two very strong assets preclinically, which is why we advanced them both into phase one to help us generate more data to determine what we will do downstream with both of these compounds. Let's get to the phase one, right? This is the phase one data summary for interim data for 719 and 451. The takeaway on the tolerability side is very well generally well tolerated, no serious adverse events, mainly mild to moderate. We had no adverse events that led to discontinuation. Even on the LFT side, we had no adverse events related to liver function tests except for one grade one, which was a subject that had the flu. Very confident in the generally well tolerated profile that we're seeing with both 719 and 451 supports BID dosing. As you can see, 451 has completed the SAD/MAD portion of the phase one. 719 just had one cohort left of 120 milligrams, but we are right on track, as I said, to deliver the top line data in the second quarter. Very excited about being able to share the full data set. What we have presented in the past is interim PK for three different cohorts or three different doses for both 719 and 451. The Y axis is the log scale of exposure. The X axis is time. What you're seeing here is day 10, the last day of dosing, the last dose we gave the subject. We know we're at steady state, and it gives us the best barometer of the exposure we're seeing. If you flash back to the HBE curve that I mentioned before, you see the two different teal hash lines. One is if you added 719 on top of Trikafta, so that's the bottom line. The top line is if we had 719 as part of a dual combination with one other compound. They're different lines, but they represent the same clinical benefit. 10 millimoles of sweat chloride improvement, three points of FEV1. They're in just two different use cases, right? One is as an add-on, so it's four drugs together. One is a dual combination, so two drugs together. In the two drug scenario, you need more NBD1 because it's only part of a dual combination to drive that level of benefit. What the takeaway you see with 719 is for all three doses that we're seeing here, we are above our add-on target, adding it on top of the standard of care. In the two doses we see here, 40 and 80, we're above the dual combination. In all cases, we've got paths forward with both an add-on and a dual combination, and we have multiple doses that can be progressed if we move 719 forward. Oh, okay. I'm seeing separation between 40 and 80 on this one. Wondering why you didn't on the other one. 451? No. Yeah, yeah, yeah. On the previous slide? Yep. Why no dose exposure? It is actually separating, what you're not. This is a log scale. It actually is more separated than you think, right? We are actually getting to higher levels, the higher doses we've gone. It is a little misleading with the log scale, but it is absolutely, you are seeing a dose response as you go up for 719. Similarly with 451, right? You can see it here. This is the second compound. The same teal hash lines as an add-on or a dual combination. The takeaway with 451, same thing. All three doses are above the target for an add-on. Even at the lowest dose here at 75 milligrams, we are right at the dual combination target, the other two well above. Both looking very encouraging from a tolerability perspective, achieving the PK that gives us a lot of optionality. The next question will be, what do we do with these two programs, which I will talk about on the CDP in a couple of slides? I did want to just touch base on the two combination assets that we are prioritizing. This is GallaCaptor 2222. What we're showing you on the graphs here is the combination study that AbbVie ran of GallaCaptor plus Navacaptor. Phase two dose response that you see here, the top part of the graph is an FEV1 comparison. If you look at what's highlighted in red, the top two doses that were tested in this combination showed an impact on FEV1 similar to Symdeko, right, in terms of what Symdeko was able to do. If you drop down to the bottom half, you see sweat chloride, same thing, meaningful sweat chloride change when combining GallaCaptor with Navacaptor. The reason I show this slide, we had this data, which is one of the reasons we did the deal with AbbVie. We knew that GallaCaptor was an active compound, had phase two level efficacy data and tolerability data, and we got very excited about the potential to add that to our portfolio. We know we can just add GallaCaptor, as I showed you on the HBE curve, and you have the potential with NBD1 to get significantly high up on the chloride transport, sweat chloride, and potentially FEV1. We are very pleased with the data that we have with GallaCaptor as a potential combination. 109 has just finished the phase one. That's one of our other combination assets. I'll just focus on the right-hand side. Very encouraging tolerability profile and PK. Its dosing will be BID, just like NBD1, but generally well tolerated, no SAEs, and continues to hit the PK markers that we set in combination with NBD1. The takeaway from the combo assets that we just showed, both GallaCaptor and 109, excellent combination options with either 719 or 451. As I mentioned, what will we do with these compounds going forward? Here is the clinical development plan going forward over the next couple of years. Where we're at, at the top half of the chart here, you see the NBD1 portfolio. We are in the first half of 2025. As I mentioned, we're wrapping up the phase ones. We'll have that top line data this quarter, as you see. What we will do, the next step in CF patients for these programs will be a phase 2a proof of concept study that you see here on the top. That proof of concept study will be adding NBD1 on top of the standard of care Trikafta. We will do a two-week study that will demonstrate sweat chloride improvement over Trikafta as an add-on. It will be a two-arm study, adding NBD1 to Trikafta or placebo to Trikafta and comparing sweat chloride improvement. What this study will do, it's really a proof of concept, proof of biology that will demonstrate the uniqueness and the differentiation of NBD1 when we add it on top of Trikafta. Because, as we said, unique and differentiated, but synergistic with the components of Trikafta that will be able to show sweat chloride improvement by adding NBD1. It will also give us an indicator of the translation from our CF HBE assay into CF patients and what we would predict. The third thing that's really important from this study is it's going to help us, we believe, with enrollment in the later stage studies. Because now you have efficacy data with NBD1 that should help give patients confidence that you're doing something unique and different with potentially incremental benefits with NBD1. NBD1 alone as well? We will not do monotherapy with NBD1 because if you flash back to the HBE curve. It'll be similar. Yeah. We're not looking for equivalence, right? We want to get to something that could drive incremental benefit for patients. That is either adding it to Trikafta or in our own dual combination where it's doing more than what NBD1 would do on its own. The top half is the phase 2a proof of concept. We'll have that data by mid-2026. At the same time, if you go to the bottom, we're going to continue to do some combination work. Some healthy volunteer combination studies. These are healthy volunteers at the bottom, which will be NBD1 plus 2222, the TMD1 corrector, and NBD1 plus 109. We're going to look at tolerability in combination. We're going to look at PK and exposure in combination. Those studies will help us determine what is the best combination that we would advance into phase 2B and beyond. That data we should also have in the middle of 2026. We have a lot of catalysts coming in the near term, both on the proof of concept and the combination work. By way of cash runway, with the illustration here of the timelines, we have cash again into 2028, thanks to the IPO. It gives us a lot of flexibility and ability to execute against this plan. I would say one other comment that I made on that early slide around unmet need. Here's a visual representation of what I was talking about before. To orient everybody, this is a sweat chloride plot of patients who were before they were on Trikafta. If you go to the far right, this is the Trikafta plot in blue. Those are all individual patients before they took Trikafta and what their sweat chloride was. The black is after they've been on Trikafta, the improvement in sweat chloride. Clearly, Trikafta having an impact on sweat chloride. The key takeaway here is if you look at that teal line that defines normal sweat chloride, 30 millimoles, you can see again, only a third of Trikafta patients, those who are on Trikafta, are achieving normal CFTR function. Two-thirds are above that line. That's the opportunity for Sionna to drive more of those patients to normal CFTR function. It's the same with Aleftreq. To wrap up, we will turn it over to John to see if there are any questions. We are in a really unique position. We are very excited about where we are today with the execution we have been able to deliver, the IPO, and the financial flexibility. We know the unmet need continues to be high, just like I showed you on that previous slide with two-thirds of patients not being at normal CFTR function. We have a novel and differentiated target that we are going after with NBD1, which creates a lot of strategic optionality as to how we approach this market. We are doing something transformational that we want to shift the paradigm in CF and provide more options for patients. As you saw on the timeline, multiple catalysts coming up, including finishing the phase one and releasing the top line data, initiation of the phase 2a proof of concept study in the second half of this year, in addition to the healthy volunteer combo initiation the second half of this year. We'd expect both of those results by mid-2026. Very well positioned, super excited about where we're at. I'll pause and see if we have time, John, for any questions. Yeah, we got a little over a minute. Wondering any questions in the room? If not, I have one. You have enough wood to chop, but thinking provability, do you have to show a combination of the parts? Can you do that earlier? What does the registration trial look like if you're going after a combo? Does it become non-inferiority on FEV1? TBD, there's a lot of discussions we'll obviously have with the FDA on what that later stage clinical studies will look like, right? You do need to show sort of the components of the combinations for sure. We have ways we can do that in the trial. For us, it's really about progress to the next step, do that phase 2a proof of concept, get the combination. Could you show that in that phase 2a ahead of time? You won't, because again, you won't have the individual monoarm, right, of NBD1, right? That could come at a later point in time, but it all will be built into the plans. We know we can execute the study. If we show what we believe we can show in the phase 2a with this improvement in sweat chloride, again, that's only going to help the engagement with the FDA and with patients as well. How well is the association between sweat chloride and FEV1? Yeah. There is a strong correlation. If you look at the CF HBE data that we have, it's about a 0.96 correlation between chloride transport and ultimately FEV1. The middle step there is translation to sweat chloride. What we historically have seen is that when you can deliver 10 millimoles of sweat chloride or higher, the correlation tends to get stronger and better. Sub-10, there's some noise factors that can play in. Our goal has always been show more than 10 points of FEV1 to drive that level of correlation. Covering Vertex for years, they always said their secret sauce was their assays. Does your assay replicate what they've publicly said, or is there some differences? Yeah. There's a lot of published data out there now on both how Vertex does it and how others do it. We're very confident we run it very similar to the way that Vertex does. One of the key secret sauce ingredients to both of our assays is the inclusion of human serum. We add 20% by volume human serum to the in vitro assay, which with highly protein-bound compounds like these helps us more closely approximate the in vivo environment for these compounds. Vertex does the same thing, 20% by volume. Where we have been able to validate what they've done externally, we've talked to the Cystic Fibrosis Foundation and have compared assumptions. We feel very confident we run it very similar, right? Our belief is the assay is not unique in that way. People can run the assay, right? You need the compounds to deliver the profile to move forward, right? That is really what we think this comes down to. Really compelling. As you laid out, a lot of things happening very soon. We are looking forward to tracking the progress. Thanks again for coming, Mike. Thank you. Thanks for having us. Thanks, everybody, for the attendance. Appreciate it.