Our next featured company is Sionna Therapeutics, represented by their CFO, Elena Ridloff. Elena, thanks so much for being here. Thank you, Brian. Thank you, and RBC for having me. Obviously, a lot coming up for you guys this year, a lot of important data. Maybe we could start bigger picture. Can you give us just the latest status update for your ongoing studies of 719 and 451, and just how we should be thinking about the upcoming data timelines? Yeah. Maybe just to lay a little foundation. At Sionna, we're trying to do something very different in targeting CF. We're targeting NBD1, and stabilizing NBD1, which is the region of the CFTR protein where the Delta F508 mutation sits, and 90% of patients with CF have that mutation. We think by stabilizing NBD1, we have the potential to provide up to full CFTR correction. There's really great treatments available today for patients. They've made meaningful advances. Yeah They only partially correct the protein. We think we have the potential to do something very different. The two programs you mentioned, SION-719 and SION-451, are our two clinical stage NBD1 stabilizers. SION-719 is in a phase IIa proof-of-concept study called the PreciSION CF study, where we're evaluating 719 on top of TRIKAFTA. That's a double-blind, placebo-controlled study that's a randomized switch design. We're looking at a primary activity endpoint of sweat chloride, and that data will read out this summer. In parallel, we're also evaluating SION-451, which is our other NBD1 stabilizer, in two dual combinations with complementary modulators. That study is looking at healthy volunteers, we're focused there to see both PK and safety and tolerability of the two combinations to drive our decision to select one NBD1-based dual combination to advance to later-stage development. That's also on track to read out this summer. Great. That's really helpful context. You mentioned targeting of NBD1. That's something that historically, that target's been really challenging to engage. You guys have shown good evidence that you're hitting it. How did you crack the chemistry? What did you guys do? How were you able to kind of overcome some of these historical challenges? Yeah, the history of Sionna actually goes back pretty deep. Sionna was founded about five years ago, but the science goes back to Genzyme. Our co-founders have been working on this biology for well over a decade now. First at Genzyme and then at Sanofi. They've spent many years really focused on this target. It's been challenging historically because it has a very shallow binding pocket, there was a lot of robust X-ray crystallography and other deep chemistry and biology-driven research that drove us to develop these NBD1 stabilizers that really had to be developed atom by atom. Typical high throughput screening was not successful in this target just due to the very shallow binding pockets. It's really been a very deep chemistry and biology-driven exercise that has taken us to where we are today with these two programs now in the clinic. It sounds like it was many years in the making. Very much, yeah. I know we've talked about the HBE, the human bronchial epithelial cell assay, in the past. I know you guys have been able to learn from others' setbacks in terms of how to optimize your HBE assays, where your modulators have looked promising. Can you talk about what drives your confidence around their translatability and what you're doing that's maybe different from what others besides Vertex have done? What might be similar to what Vertex has done that's fostered success for them? Yeah. The HBE assay is a cell-based assay that was actually developed in academia. It's been honed, it's important that you run it in a rigorous way. Our team, again, going back to Genzyme and Sanofi, and now at Sionna, has been running this assay for quite some time. The key piece to it is that you have to ensure that you're really reproducing the human biology when you're looking at your dose predictions from the assay and your concentrations needed in humans. One of the key pieces is to ensure that you're putting in serum, human serum into the assay. That's something that has been published that Vertex does, that we do. We also collaborate with the Cystic Fibrosis Foundation, who has a lab and runs this assay. From everything we know in the public domain, from how the CFF runs the assay, how Vertex runs the assay, we believe we run it in a very, very similar way. We've run the approved modulators through our assay, and we've reproduced their clinical findings. That's another validation for our assay and our assay predictions. There have been other companies that have not been successful in CF, and it's not necessarily that the assay failed. It may be that those molecules specifically didn't fail either. They had tolerability challenges. Bio-distribution. Right. Therapeutic window. achieve the PK needed based on assay predictions. We don't think that's necessarily an assay failure, but those could have been compound-specific failures. Makes sense. Can you tell us a little bit more about your compounds? You've run some phase I healthy volunteer PK/PD studies. What are some of the key learnings there in terms of just the PK properties and half-life dose dependence of exposure, et cetera, that gives you confidence you're going to be able to get to those target concentrations in the phase IIs? Yeah. We completed phase I studies last year, the focus of those studies were to achieve specific PK targets that we have based on the HBE assay, where we believe we can show a 10 millimole improvement in sweat chloride versus the standard of care. In each of our use cases, for example, for 719 as an add-on to TRIKAFTA, and for 451, our dual combinations, we have specific assay concentrations that we're looking to achieve in phase I PK- Correct that would deliver that. We reported that data out last summer that we showed that with both programs, we exceeded our PK targets for both 719 and 451. That was what led to this advance for both compounds in the next stages, as I discussed. Both drugs, the PK profiles of both of them support BID dosing. That's how we're evaluating both drugs. Got it. Maybe going over to the 719 phase II study, I know we'll see the readout in the next few months. You mentioned 10 millimole as the sweat chloride bar that you guys had sort of aimed for as you thought about dosing dose levels and kind of mapped it to the PK from the phase I. I guess, can you talk more about what shapes your bar for what would be a meaningful difference in sweat chloride? What do you need to show on that biomarker to be confident that this will ultimately translate to functional benefit on FEV1? Yeah. We've set the threshold and the bar as 10 millimole improvement in sweat chloride, for a few reasons. One, when we speak to the community, to clinicians, and KOLs, consistently, that's what we hear back as the level that would really excite them as far as an improvement in sweat chloride. Historically, as you were speaking to, ultimately, the approval regulatory endpoint in CF has been FEV1. If you look at studies historically that have delivered a 10 millimole or more improvement in sweat chloride, those largely have translated into an FEV1 improvement. With about a 10 millimole improvement, we would anticipate something like a three-point improvement in FEV1 in larger studies in later stage development that are powered for FEV1. The PreciSION CF study is designed to look at sweat chloride. It's too small to look at FEV1. Sure. Importantly, our PK supports the fact that we think that we can deliver that 10 millimole improvement. That's really all the reasons why we've really honed in on that as a target. Got it. What does the safety bar look like for the phase II? What are you guys specifically looking for? This is a randomized placebo-controlled study. We're targeting about 16 patients. Each patient will serve as their own control. It's a randomized switch study with a washout from the NBD1 or placebo in the middle. We'll have their safety and tolerability on their background TRIKAFTA plus placebo versus 719. The goal would be to have a risk-benefit profile that supports advancement if we were to decide to advance the add-on. TRIKAFTA does have its own tolerability profile. We have selected a low dose in this study because the goal is not to add any tolerability challenges beyond what's seen with TRIKAFTA. I know you guys are looking at FEV1 really more from a safety standpoint, just given the small size and short duration of this study. I guess, are there any mechanistically plausible scenarios in which the biomarker data, the sweat chloride data maybe look a little bit variable or inconclusive, but there might actually be some trends on FEV1 that you guys are able to detect? Yeah. Without speculating on that hypothetical scenario, I do think this study is, as we've said, too small. FEV1 can be very variable. We are looking at it as a safety endpoint, but this isn't a study powered to look at FEV1. Sweat chloride does have less variability, that's why we've designed this study to look at sweat chloride. Got it. You're going to have several readouts now in the coming months, so you'll have a kind of a good sense of the profile of your assets and where to take them. I'm curious, what are some of the key things that you guys are going to be looking for in both the 719 readout in CF patients as well as the 451 healthy volunteer combo data in order to determine which to move forward and in what settings to do that? Maybe I'll start with our dual combination. The goal of this study is to look at the PK and safety and tolerability of each of the duals, and to be able to evaluate them versus the other option, to select one dual to advance to the next stage of development. With the add-on, with 719, the PreciSION CF study, there's a few things that that study will really show us that we think will also help inform our dual strategy. There, number one, we're looking to show and validate the NBD1 biology, that it's unique and additive to the existing mechanisms. By adding NBD1, you can further lower sweat chloride. This will be another proof point to really validate our HBE assay with our NBD1. There, we think, having that combination of PreciSION CF data will help give additional confidence in our assay predictions. Right for the dual that we're selecting. Okay. These two data sets really do kind of work together. Interplay. Yeah. That was going to be my next question is sort of, how much read through this 719 biomarker, the sweat chloride data, has for 451, just in the potential to validate the assay and the target in either direction. Is there a reason that 451 could work if 719 does not? If 719 doesn't show sweat chloride, would that sort of change the bigger picture strategy for both stabilizers? Yeah. It's a good question. We're very confident in our predictions for the assay for 719 and the outcomes of that study. If we were to not achieve what we expect to achieve in that study, we'd have to look at why. There's still certainly a plausible reason where we've validated the NBD1 biology, we validated the mechanism, we validated the assay, but maybe there was increased variability or something. We would have to just see the why. There is a possibility that we could fall short of our expectations. Sure in the PreciSION CF study, but still have a lot of body of evidence that would support the dual strategy. It really depends on the data. It all depends on the data. what you see. Yeah. Thinking a little bit further ahead, what could a phase III or pivotal path look like for a Sionna next generation cocktail? Do you envision this would be a head-to-head study versus existing standard of care? Would you need to show superiority? Could you show non-inferiority and provide an alternative? Are there certain populations that maybe can't tolerate TRIKAFTA or ALYFTREK, or don't do well on them, that could provide sort of a different path to market? I guess, how are you guys thinking about the development path? Because obviously CF is a huge market, but there is a very entrenched- Yeah dominant player. How do you think about sort of breaking through that? Yeah. One of the great things about this market is that there is an established regulatory pathway. Even with ALYFTREK getting approved more recently, there they went for a non-inferiority approach. Based on everything we see today, we believe we have the potential for superiority, and so we would be looking to design studies that showed that. If for some reason data down the road were to look different and we think that we're looking for non-inferiority, there's a registration path for that as well. We'll be very data-driven. Based on the data we have today, we believe we have that potential for superiority, as I said, and we would be designing those studies to look at that. Okay. Is there any particular subpopulation within CF, be it patients with certain mutations or certain FEV1s, that could be most optimal to really demonstrate the advantages of a Sionna cocktail over the existing standard of care? I know it's a little bit premature to know for sure because we haven't seen the data yet, but just as you're thinking about where you can differentiate and show the best advantage, and kind of thinking about the NBD1 stabilization mechanism overall, where is the biggest unmet need, I guess? Yeah. 2/3 of patients today do not have full CFTR correction. There is a very big population of patients who could do better. In addition, there's a big population of patients who don't tolerate the existing standard of care today as well. There's something like 20% of patients who either discontinue or dose adjust their treatment today because of tolerability challenges. We do think there's a tremendous unmet need, where a new option as a dual, or if we were to continue to progress the add-on, also that add-on to get more patients. Got it. to normal. We think there's really compelling commercial opportunities for both the dual and potentially the add-on as well. As we think about the registration path, we don't think that there's some subset that we'd have to look at. We really do think this is for the broad population of about the 90% of patients that have at least one Delta F508 mutation. That's the way we're thinking about the development strategy. How do you think about this idea of add-on versus full proprietary cocktail? I know in the past you've talked about one asset maybe being more optimal for an add-on, the other asset being more optimal for a combo. I guess just could you swap them around? Would you first go after just the add-on or first go after the head-to-head full cocktail strategy? Yeah. What strategically is your prioritization? Yeah. We're in a fortunate position where we have strategic choices. Right which is always great. Right. Because both 719 and 451 both looked so compelling after the phase Is, we decided strategically to make this choice where we're advancing 719 in the proof of concept study, and 451 is the backbone of our duals. You could certainly have done that with one of those compounds, but just because both looked good, we had that opportunity. Yeah. To select different molecules for the different strategies. Our prioritized path we've said is our dual combination. As we thought about the capital we have today as a company for the next phase of development, we've prioritized our dual because we really think having a dual combination that is novel, that is an alternative to the standard of care with the potential to have superior efficacy is a very compelling opportunity for the community. As we think about the add-on, there's always going to be patients who are happy on their existing therapy but Yeah ..could still benefit from more efficacy. Yeah. There is also a compelling opportunity there. If we achieve that 10 millimole improvement in sweat chloride, what we've said is that will be more of a capital decision, because if we were given the opportunity, we would like to progress that as well. Yeah. We want to prioritize our capital as a company today for the dual. Got it. What do you think you would need to show ultimately, obviously statistically significant superiority would be important, but what do you think you'd have to show in terms of an FEV1 benefit over TRIKAFTA or ALYFTREK to have commercial success for a Sionna dual combo? Do you think there might be other creative ways that you can show that even if there is some theoretical ceiling on lung function effect, that you can show that better CFTR modulation and correction can have better systemic effects where patients are going to do better on your dual than the old Yeah standard of care? We firmly believe we could deliver a superior profile. Yeah. Again, we've defined that as about a three-point improvement in FEV1 based on what has been historically meaningful for some of the earlier modulators that were approved that met that regulatory bar and drove meaningful commercial products. What we hear from the community is there's really a desire for more options for patients. Even if we were to not hit that hurdle, we think there's a meaningful opportunity for our product, just like we're seeing with ALYFTREK today. That product was non-inferior on- Right FEV1 and is tracking. Yeah to be a very sizable commercial product. People believe that the sweat chloride shows a difference. Yeah. Yeah. Again, we certainly believe that we have the potential to deliver that superiority, and we think that is a really compelling opportunity for patients to have a novel dual that could be superior-. Yeah to standard of care. We hear a lot of enthusiasm about that potential profile. Okay. Can you make the drugs into once-a-day versions? Do you think that'll be possible down the line? Does it matter? I guess the TRIKAFTA stickiness as a BID drug would suggest that maybe it doesn't really matter that much in CF, but if a few years from now, ALYFTREK, which is a once-a-day, does gain more share and traction, I guess does it make the bar higher to bring a patient from a once-a-day to a twice-a-day in terms of what you need to show on efficacy? Are there ways you could get these to- Yeah once a day anyway? Based on the current profiles of the products, we expect them to be twice a day. Again, when we talk to the community and physicians, we don't believe once a day versus twice a day is a meaningful driver. We really think it's an efficacy-driven market, and so if we're able to deliver the efficacy profile that we believe we'll be able to, we think that'll be a compelling profile for patients. Okay. Good. Maybe just to wrap up, I guess what would shape your strategy on whether to bring your assets forward independently versus to seek a potential partner that maybe has commercial infrastructure that's leverageable? Yeah. One of the great things about being in the CF world is the patients are well identified. It's an activated community that are treated largely at CF Centers of Excellence. This is certainly a therapeutic category that Sionna, as a company, could execute fully on our own. We've brought in already a lot of great expertise, and something we expect we could continue to prosecute on our own. Of course, we'll always consider if there's partnerships or things that could make sense down the road. Yeah We would consider that, but we feel like we can really create a lot of value by continuing to advance these compounds on our own, and commercially, it's an attractive market that we could do as Sionna. Makes sense. Well, we're out of time, Elena, thanks so much. Thank you. for being here, and really looking forward to the coming months. It'll be an exciting back half of the year. Thank you. Same here. Thank you.