Welcome, everyone, to the Sionna Therapeutics presentation here at the 45th Annual TD Cowen Healthcare Conference. I'm Senior Analyst Ritu Baral, and presenting for Sionna is CEO Mike Cloonan. After the presentation, we'll be doing guided Q&A with audience participation as well. Mike, thank you. Thanks, Ritu, and thank you, TD Cowen, for the opportunity. Thanks, everyone, for joining this afternoon. Pleasure to have the opportunity to talk to you about Sionna today. As Ritu said, I'm Mike Cloonan, the CEO, and I'm going to take you through a handful of slides, probably about 15 minutes of presentation, and then we'll turn it over to Ritu for Q&A. We are going to be making forward-looking statements. Actual results may differ from those forward-looking statements. Just a quick overview of the team. I am Mike Cloonan. I am joined by Charlotte McKee, our Chief Medical Officer, and Elena Ridloff, our CFO. The two other members of our team that are not here that I do want to point out, Greg Hurlbut and Mark Munson, our two co-founders, part of the reason not only giving them credit for what they have founded in Sionna, but also to give you a little bit of the history. If you look at the common denominator between Greg and Mark, Sanofi. That is where Sionna spun out in 2019. We came out of Sanofi, but the science goes all the way back to Genzyme. We've been working on these programs now for over 15 years between Genzyme, Sanofi, and Sionna. We wouldn't be where we are today in Sionna with multiple clinical assets against a very challenging target, an NBD1, without that legacy and the level of investment that was made prior. Because we do often get asked, how did Sionna crack this target of NBD1? A lot of that speaks to the history that we have and the level of investment and perseverance, not only of our team, but now in three companies that have worked on this. Now let's talk a little bit about Sionna. I'm sure many of you know what we are focused on, which is cystic fibrosis. We are really looking to revolutionize the treatment in CF by going after a new and differentiated target called NBD1. Let's start first with the CF space. I'm sure many of you know CF is a large market, $11 billion market today, that is growing to $15 billion in the near future. Vertex has made tremendous advancements over the past decade or so. We give them a lot of credit for what they've done for patients. What we also know is that the unmet need continues to be high in this space. One of the ways we define that is through CFTR function. We know that for two-thirds of patients who are on the standard of care today, they are not achieving normal CFTR function. That's our goal, to drive as many patients as possible to normal CFTR function. If we can do that, if we can deliver more options for patients that could provide clinically meaningful benefit to them, not only is that outstanding for patients, but it is a large opportunity for the company and for our investors and all stakeholders within CF. One of the ways we're going to focus on is through NBD1. I've referenced this before. This is not a new target within CF. It has been studied for a long period of time. The biology is well understood. For many years, it was considered undruggable, mainly because of the very shallow binding pockets that exist around NBD1. Now, we'll get into the biology of NBD1 in a second. What is important about NBD1 is we believe it gives us the opportunity to fully correct the CFTR protein. If you can fully correct the protein, you can fully normalize its function. None of the approved modulators today directly stabilize NBD1. It is differentiated and novel. The third key part of our story is we do leverage the industry standard CF hBE assay. This is a very important part of our strategy and how we develop our compounds. We'll share some of our hBE data today, but this is a clinically validated in vitro assay. What we'll show you in our assay is the potential and the power of NBD1, both as an individual component, but also in combination, that shows us the potential that we have in entering the CF market. The fourth key part of our story, as much as NBD1 is really that foundation and that differentiation that we have, we're also developing a pipeline of complementary mechanisms, combination assets. The path here for us to commercialization is combining NBD1 with something else. We have a portfolio of combination assets that we can utilize with NBD1 that has the potential to deliver fully normal CFTR function. Those are our four key highlights of the company. Let's talk about NBD1. I'm going to focus on the bottom right here, the graphic, the cartoon of the CFTR structure. We know what causes CF, genetic mutations to the CFTR gene that impacts the CFTR protein. You can see the CFTR protein has different regions or domains. NBD1 is that bottom left portion that you see there. If you look at that little green circle inside of NBD1 that's labeled F508del mutation, that is the number one genetic mutation that causes CF. For approximately 90% of patients have a form of the F508del mutation. Again, it resides within the NBD1 region of the protein. What that mutation does is it causes NBD1 to irreversibly unfold at body temperature. It is creating this instability in the protein, crippling the folding, the trafficking to the cell surface, and then the overall functionality of the protein. Now, what the Vertex compounds do is the triple combination of TRIKAFTA corrects ICL4, TMD1, and TMD2. It's correcting around NBD1, not directly stabilizing NBD1 where the problem exists. It's really partially correcting the protein. TRIKAFTA is a good drug, but it's partially correcting the protein. We believe there's more room to go by stabilizing and correcting NBD1 and providing a different mechanism of action for patients. This is where we believe we have the potential to drive more patients to fully normal CFTR function. Let's talk about our pipeline. I've talked about NBD1 and the complementary mechanisms. We do think of the pipeline in two dimensions. The top half is the NBD1, the differentiated part of our portfolio. There are two different compounds going after NBD1, SION-719 and SION-451. They are both in a phase I healthy volunteer study now. We have interim data that I'll share in a few slides. The key takeaway you're going to see from the phase I data is that for both of these compounds, with the safety and tolerability profile that we have today and also the exposure PK that we've achieved, both of these compounds are enabling our target product profile of what we call a dual combination that has the potential to add clinically meaningful benefit over the standard of care. Combining one other compound with either one of these assets gives us a potential to drive a new and beneficial option for patients. We'll share that data with you. We're going to let the rest of the phase I data play out before we make a strategic choice on how to advance these compounds. The positive note from that phase I is both of these compounds are advanceable based on what we see. We're now going to choose from two different positive options. The bottom four programs you see here are the combination assets that I mentioned before. The three star assets, you may have seen we did an AbbVie in-license deal last year where we in-licensed three clinical stage assets from AbbVie, galicaftor, SION- 2851, and navocaftor. Galicaftor and navocaftor have phase II level data and are very good combination assets with NBD1. We also have our own ICL4 corrector, SION-109, that has finished phase I and is also looking like an excellent combination option with NBD1. When we look at our portfolio, we have six clinical assets here. The goal is to narrow down the NBD1 portfolio to our best option between SION- 719 and SION- 451. 451. We're going to prioritize galicaftor and SION- 109 as the combination assets to put together with that chosen NBD1 compound. That portfolio will come down from six to three over time. That is the portfolio. Strategically, I have sort of referenced this, but it is always good to back this up with a visual. We have many different ways we can enter this market because of the differentiation of NBD1. If you look at the bottom first half of this, one of the ways we can enter the market is just by adding an NBD1 stabilizer to the standard of care. As you saw on the biology slide, NBD1 is different from, but yet synergistic with the components of TRIKAFTA. We could just layer NBD1 on top. We think about that option as really our minimum product profile. We could achieve that by just layering it on top, but we do not ultimately think that is the best commercial path or the path that could be most beneficial for patients. That path is the top path, which we consider our target product profile. This is the dual combination. This is Sionna proprietary combination that can compete directly with Vertex, but in a dual combination as opposed to their triple, and where NBD1 is the foundation asset of that combination. When we share the phase I, both of these paths are enabled with SION-719 and SION-451. We could choose either path, but the higher bar is that target product profile that has been achieved in that interim data of phase I. We are very excited about the phase I potential of both of these programs, that both options are in play. Just to give a couple of updates on recent events, I'm sure you saw we just recently had our IPO earlier this month. I think it's just over three weeks since we completed the IPO. We raised $219 million. We're thrilled with the level of investment that we have now. That takes us into 2028 in terms of cash runway. We've continued to execute on our pipeline, as I've mentioned, with the phase I programs on NBD1 and the rest of our portfolio. We've got those combination assets thanks to that AbbVie deal that really gave us depth and breadth to the pipeline. We've really executed very strongly over the last 6 months-12 months that put us in a position to execute the IPO. We're looking forward to the coming next 6 months-12 months as we continue to advance our programs. Let's talk a little about our lead program, SION-719 and SION-451 for NBD1. I talked about the assay, and I did want to share some of this pre-clinical data just to orient you around the potential of NBD1. For many of you who know, the CFHb assay, again, is the industry standard in vitro assay. It measures chloride transport on the Y-axis. What we have done is we see here the 1.0 on the Y-axis. That aligns to that black circle of elexacaftor, tezacaftor, ivacaftor. That is TRIKAFTA. That is the baseline today. We have modeled all of the Vertex compounds in our assay. Those are all the black dots that you see. Our assay results match the published clinical results of Vertex. We have a lot of confidence in the predicted power of our assay. This is the anchor, right? This is TRIKAFTA today and where it sits. If you go just below and you see that red dot that says SION-719, that is the monotherapy. That is the single agent SION-719 in the assay at Emax compared to TRIKAFTA. You can see just below the triple combination as a monotherapy. That shows the potential and the power of NBD1 as a single agent. What we have always said is we want to drive meaningful clinical benefit above TRIKAFTA. The way we can do that is through combination. If you go up the curve, you can see two different dual combinations that I have referenced before. SION-719, one of our NBD1 stabilizers, plus SION-2222, one of the AbbVie assets, or SION-719 plus SION-109, our own ICL4 corrector at Emax all the way up until wild type levels of CFTR function. The potential is there with NBD1 to disrupt this space in a positive way. What we also look at is that would be tremendous, right? If we can deliver that level of efficacy and get patients to wild type and fully normalize CFTR function. What we also said is, what's the minimum bar? What's the minimum that we want to be able to deliver to show we can add clinically meaningful benefit over TRIKAFTA? If you see this teal hash line there, that's what it's labeled. That's our minimum target as we went into the phase I that we said that's the bar we need to achieve to demonstrate meaningful benefit over TRIKAFTA. If you look at what that bar represents, it represents a 10 mmol/L sweat chloride improvement over the standard of care and three points of FEV1 improvement. We know that would be meaningful based on our interactions with KOLs from Charlotte's experience having worked at Vertex and in CF in the past and the community. They have told us consistently, if you can deliver that profile, that would be a meaningful option in CF. When I share the phase I curves, remember that teal line I'm sharing you there because we're going to superimpose that on the phase I curves to show you what PK looks like relative to that target. Similarly, this is SION-451. This is the second NBD1 compound that you saw in the pipeline slide. Very similar profile. Monotherapy, nearly equivalent at Emax to the components of TRIKAFTA. In dual combinations, the potential to get all the way up into wild type. This is why we pushed both compounds into phase I. Pre-clinically, they both look like excellent options. We wanted to generate more data in humans and help us determine which of these compounds could ultimately rise to the top. That's the pre-clinical. Now let's flip to the clinical data, which are our phase I study. I mentioned both of these compounds are in a healthy volunteer study. The key takeaways you're going to see is this middle part here where the dosing has been very well tolerated to date. No SAEs, no adverse events, or most of the adverse events were mild to moderate. And PK has been consistent. This represents BID dosing. We've achieved those concentration targets that I said that imply our ability to deliver a dual combination that could be very competitive in CF. I'll give you a little more detail on both of those compounds, but that's the key takeaway. This is the MAD curve. This is the multiple ascending doses that we're using here. This is SION-719. This is day 10. It's a 10-day study in healthy volunteers. This is now at steady state. You can see the concentration on the Y-axis and time on the X-axis. You see the two different teal lines. That is that minimum target I was referencing before, but in two different ways. The bottom teal line represents the target if we added NBD1 on top of TRIKAFTA, which is a lower target because now you are putting four compounds together as compared to the higher target, which is the dual combination, the Sionna proprietary combination of NBD1 plus one of our combination assets. The takeaway you see from this slot in three, this is interim data, but with three different doses for SION-719, two of them are well into our concentration zone of the dual combination. All three of them enable the add-on to TRIKAFTA. The top two doses of 40 mg and 80 mg are above our dual concentration target. This is what got us excited again about this early phase I data. We're already in a position to say we can deliver our target product profile with this compound. This is a little bit more background on SION-719. Again, no SAEs. Most AEs were at mild to moderate. No discontinuations, no dose-limiting AEs, and also no AEs related to liver findings. This is a small molecule, so that was a very important takeaway for us as well. With SION-451, similar plot that I'm showing here, the second compound, SION-451, the same lines that you saw before, the teal targets of the add-on and the dual combination. For here, we have a little bit higher dosing with SION-451. What you can see is with that blue first dose of 75 mg, we're right on the cusp of that dual combination target. With the green and the blue at the higher doses, we are well above the CAV target. In every case, we're above the CAV as an add-on. In the two higher doses, we're well above that target product profile of a dual combination. Both of these compounds are looking very encouraging from a PK exposure perspective. The safety of 451 is very, very similar to what you saw with SION-719, very well tolerated. The only adverse event we've seen with a liver signal was in SION-451 at the 150 mg dose in a patient that had the flu. We did the 300 mg dose for SION-451, and we saw no adverse events related to liver. These are very strongly tolerated programs in both SION-451 and SION-719. I am very encouraged. Now let's talk a little about what we're going to do with these compounds. I've talked strategically around how they're going to come together. This is our clinical development plan. The top half is NBD1. You can see two different studies ongoing. We plan to finish the phase Is for SION-719 and SION-SION-451 in the first half of this year. By the end of Q2, we should finish both those programs. The plan is to select the best compound that we would advance. From there, what we would do with that lead NBD1 compound is we would then put that into a phase II-A proof of concept study where we would add NBD1 on top of TRIKAFTA. Remember, that's our add-on strategy, but it's not our commercialization strategy. This is truly going to be a proof of concept, proof of biology study that will show the benefits of adding NBD1 to TRIKAFTA. The goal here will be to measure sweat chloride improvement to show there's more room to improve CFTR function and that NBD1 is truly differentiated from the components of TRIKAFTA. It will also help us enroll the phase II-B studies because now you'll have efficacy data that will show what the power and the potential of NBD1 is. Lastly, it will also help us demonstrate the translation of that hBE assay to real-world data in CF patients. We'll be able to map those two things back together. A very important study that we'll read out in the first half of 2026. By mid-2026, we should have that proof of concept data. While that is going on, again, that's the proof of biology, proof of concept study. We will also be doing combination healthy volunteer work with our dual combinations. We'll take that lead NBD1 program, we'll combine it with SION-2222 from AbbVie and our own SION-109 program, and we're doing some combination work to optimize the dosing and the exposure of those combinations that we ultimately select the best combination to put into a phase II-B into 2026. Lots of milestones in the near term as you think about the completion of the phase I, the selection of the compound, the initiation of the phase II-A, and also the initiation of the combination MAD. Lots of data that will be generated showing the power of NBD1. The last slide I'll do before I wrap up is we always like to contextualize the unmet need. I talked a little about this CFTR function and that two-thirds of patients on the standard of care are not achieving normal CFTR function. Just to orient you to this slide, this is from a post-marketing study that was done on TRIKAFTA and others to say, what was the improvement over time in sweat chloride? The right-hand plot there is TRIKAFTA. The blue is patients before they were on TRIKAFTA, what were their sweat chloride levels. The black is when they're on TRIKAFTA and where the sweat chloride went to. Clearly, an improvement from TRIKAFTA, right? You give TRIKAFTA a lot of credit. What we point out is that teal line there that represents normal CFTR function, which is a level of 30 sweat chloride, only a third of patients are achieving normal, even on TRIKAFTA. That is really what that unmet need represents is all these patients above that line, that is where we think we have an opportunity to drive even more patients to normal CFTR function with NBD1. Very important visual. Lastly, just to wrap up, and we'll turn to Q&A. We're very excited about the opportunity we have at Sionna. We think the unmet need continues to be high, just like that last slide I saw in this $11 billion market that is growing. More options for patients are needed, new mechanisms are needed, and we can get there through this novel mechanism of NBD1. It creates a real opportunity for us to do something unique and differentiated to drive more patients to normal CFTR function. Lastly, as I said, we're well positioned from a cash perspective and our execution, and we have many near-term catalysts that will enable us to demonstrate what NBD1 has the potential to do. Let me stop there and pause, and then we'll turn it over to Ritu to facilitate the Q&A. Thanks, Mike. Maybe we'll start with a question at the very beginning that stems from the very beginning of your presentation. Why was NBD1 considered undruggable? And what is the secret sauce that resided at Genzyme that your founders took? Right now, does your market intelligence suggest that there is any other NBD program in development? Yeah, history. Let me talk to the history of it too. This has been a challenging target. If you look at the background here, there have been other companies that have tried to crack this, one of which was Pfizer that wrote a paper about NBD1. The takeaway has been the very shallow binding pockets that exist for NBD1, very challenging target to bind to. This is a very challenging medicinal chemistry exercise. For many years, it was considered undruggable because of these shallow binding pockets and nobody being able to bind or drug this target. At that time, as you mentioned, at Sanofi, there was perseverance that played out throughout this whole process, that the finding out where to bind with NBD1 was not a traditional process of high-throughput screening or other tools that you would typically use. It was structure-based biology, right? X-ray crystallography, other ways of really determining where and how we are binding to NBD1, and then over time, building these atoms up or these compounds up atom by atom to demonstrate efficacy and activity in the assay. When you step back, I'd say structure-based biology, Ritu, is a big part of this, and then just the level of investment and time that it took to crack the code. Again, this is why I spoke to the legacy of these programs, and this is 15 years in the making, 10 of which were before Sionna was even formed, that we are benefiting from that today, right? That level of big pharma investment and stick-to-itiveness, and then the team. The team has been together for that period of time, and the learnings that we've been able to apply over that decade plus have been really important to the success. To your question around, are we the only one, right? What we know today is that when we do extensive IP searches, there's nothing else that comes up with NBD1. We continue to believe we're the only one doing NBD1 and have programs related to NBD1, but that's what's out in the public realm, right? We can never be certain, and we're not going to take that for granted. We're going to continue to innovate as it relates to NBD1 and build out our portfolio because we think this is such an important target. We're going to continue to optimize around NBD1, but we'll continue to monitor the space. Everything we've seen here is that we are unique, and we do have a great relationship with the Cystic Fibrosis Foundation that they give us, just broadly, have said that you are unique and that no one's doing what you're doing. They're not going to reveal what any one company is doing, nor should they, but we feel like we're in a very strong position today as it relates to NBD1. Your questions in the room? Can I just ask about the relationship with AbbVie? Yeah. These were the assets that AbbVie chose not to take forward. If I remember rightly, that was because they could not offer a benefit on top of Vertex, not for any other reason. Just where it stands with, do they have any rights to this, to your product going forward, and just more background on that? Yeah, let me talk to the background of why AbbVie made the choice, and I'll turn it to Elena, and she can talk about some of the economic terms. Historically, you're right, what ended up happening, these assets, AbbVie's assets came from Galapagos, right? They had worked on them, and then AbbVie took them over. What AbbVie had is they ended up, the two assets that we talked about before, navocaftor and galicaftor, those are two of the AbbVie assets that we licensed. At the time those were being developed, when AbbVie was going after a competitive play in CF, it was at the time when Symdeko and Orkambi were the standard of care before TRIKAFTA. At that time, the standard of care was a dual combination. AbbVie actually had a competitive dual. Symdeko, sorry, navocaftor and galicaftor together actually were competitive, when you look at the clinical data, to Symdeko and Orkambi. TRIKAFTA launched, right? They raised the bar. They now raised it with a triple combination from the double combination. What AbbVie then had to pivot to is we need to now be competitive with TRIKAFTA, and they needed the third compound, which was an ICL4 corrector that they tried to develop so that they could be competitive with TRIKAFTA. They could never get the third compound to be as efficacious as TRIKAFTA. I think they tried multiple times and just could not quite get there. But they had very good assets, and that is we were able to work with AbbVie and pick through the assets that we saw were very beneficial in our hands and with NBD1. But historically, AbbVie gave it a really strong go and just could not get that third compound to combine with their dual combination. I will let Elena talk through the economics and the relationship. Yeah, so AbbVie has late-stage development and commercial milestones on the assets we licensed from them, as well as royalties. Those royalties range from high single digit to low double digit in aggregate, and those are only on the compounds we licensed from AbbVie, not on our NBD1s. I would just say AbbVie was a very good partner through the process with us, right? They very much understood the need to continue on with the work that they had done and put it in somebody else's hands that maybe could extract more value because of NBD1, but they've been a great partner. Other questions from the room? Is there anything you could see in the TRIKAFTA combination study that would maybe shift your strategy to say, is it a commercially viable path? Adding it on to TRIKAFTA? Yeah. If we mentioned it's more like a proof of concept. Yeah. If it results at a certain level, would you actually? Yeah, that's a great question. The question was, would we ever take the add-on strategy and commercialize it, right? Not just the dual combination. I'd say right now, what we've said is that we think that's more of a proof of biology, proof of concept, because we think the dual combination is ultimately what is the best commercial path, right? That's what we think gives patients the best option. It's two compounds coming together that have the potential to add meaningful benefit. Having said that, to your point, we'll always follow the data, right? We'll follow the data. If that add-on approach looked phenomenal, we would think through that. It's a capital question in many ways, more so than it is a strategic question. There was nothing stopping you from commercializing that path. It's just more, can you commercialize from a capital perspective two distinct paths of an add-on and a dual combination? Again, it's not something that we are limited in doing. It's more trying to be as capital efficient and at the same time pick the best option that we think is best for patients. Absolutely, always follow the data, and we'll run that study, and we'll see what it tells us. Other questions? From your perspective, and Charlotte, we'd love your perspective as well, what are the greatest areas of unmet needs for CF patients? As we've done our diligence on the CF space, it's clear that TRIKAFTA is great, but obviously, it's not disease-correcting. What are some of the areas where, as you think about phase II and phase III, endpoints that could capture differential benefit? Go ahead, Charlotte. We are laser-focused on improved efficacy. Mike showed you that slide of the CFTR function distribution from the CFF, and that really is where, as you look over the history of CFTR modulators, as the waves of modulators that are approved have improved, those have provided short-term and long-term increased benefits to patients. On FEV, right? On FEV1, on things like BMI, on things like pulmonary exacerbations, on long-term endpoints like lung transplant rates, like ultimately FEV1 rate of decline. Short-term and long-term endpoints. That really, that is the suite of long and short-term endpoints that we anticipate being able to modify if we really can move the needle substantially and bring most patients into the normal CFTR function range. Simply, what we are hearing also from both the literature and from thought leaders is, above and beyond that, an alternative. The profile of the approved modulators has some areas that could be where alternatives could be beneficial. From a tolerability perspective, we all know there are known in the labels, there are known increases in liver function tests. With TRIKAFTA in particular, there have been some CNS-related challenges, both in the European label and in the literature. All of that will become, we'll be looking at those things with our compounds through our development program. That is where we think perhaps two molecules versus three coming together could potentially be an advantage. As we think about improving CFTR function, that in itself is a non-approvable biomarker. What is, sorry, as we think about improving CFTR function, what's the delta on CFTR? Because that will be the endpoint of the next trial that you are shooting for that is most likely to translate into exactly what we just talked about. Yeah, so we expect the registration endpoint still to be FEV1, as you said, and that really is the framework that we're working within. If you look at, for example, the AlephTrack phase III data, obviously FEV1 was not inferior. How we see those data are that the CFTR function improvement that was seen versus TRIKAFTA with AlephTrack, we don't see that as being. It was like six. It was a three and an eight depending on which phase III study versus TRIKAFTA. Those to us don't seem to be substantial enough to reliably be able to translate into improved FEV1. Our goal will be. Because it was not inferior FEV1 with those small single-digit differences. If you look across the history of trials with CFTR modulators, that 10 and under CFTR function sweat chloride range has sometimes been a risky zone. Sometimes FEV1 has improved, but sometimes it has not. Our goal is to really be shooting for something that is substantially. Right. Our phase II study will be powered for at least a 10 millimole change in sweat chloride. Great. With that, we are at time. We might even be over time. Thank you, Mike. Thank you, Charlotte and Elena. Thanks for talking. Thank you. Thanks, Ritu.