Good morning and welcome to the Sionna Therapeutics conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be an opportunity to ask questions. To ask a question during the session, you will need to press star one one on your telephone. Please note that this event is being recorded. I will now turn the call over to Juliet Labadorf, Senior Director of Investor Relations. You may begin. Thank you. Good morning and welcome to Sionna's conference call to discuss positive SION-719 and SION-451 phase I data. Joining me this morning are Mike Cloonan, our President and CEO, and Charlotte McKee, our Chief Medical Officer. Also joining us for the Q&A session is Elena Ridloff, our Chief Financial Officer. Following our prepared remarks, we will open the call to questions. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I will turn the call over to Mike Cloonan, our CEO. Thank you, Juliet. Good morning, everyone, and thank you for joining us today. Earlier this morning, we announced positive phase I data for our NBD1 stabilizers, SION-719 and SION-451. We are very excited to be in the fortunate position to advance both compounds based on their compelling profiles. We will be discussing these data and our development plans in more detail on this call. At Sionna, we are focused on establishing a unique and clinically meaningful option in cystic fibrosis. There are four key elements to our approach. First, this is a disease of high unmet need in a large market. Despite advancements that have been made in CF treatments, the majority of patients do not have normal CFTR function. Even on the standard of care, only 1/3 of CF patients are achieving normal CFTR function, leaving approximately 2/3 of patients who are not at normal. This is where we believe an opportunity for improvement exists: to drive more patients to normal CFTR function by targeting NBD1 and providing significant clinical benefit for people living with CF. There is a very large commercial market in the CF space, which is over $11 billion today and continues to grow, which presents a significant opportunity for Sionna. We believe that targeting NBD1 is the key to fully normalizing CFTR function. NBD1 is not a new target. The biology and its connection to CFTR correction are well understood. However, NBD1 has long been considered undruggable, primarily due to the very shallow binding pockets that exist around the NBD1 region. We are the first company to bring NBD1 compounds into the clinic, and the data we will discuss today reinforce our potential to deliver a first-in-class approach to enable more patients to achieve normal CFTR function. We also know that none of the approved modulators directly stabilize NBD1, so it is truly unique and differentiated. The CF human bronchial epithelial, or CF HBE assay, is also critical to our strategy. This in vitro assay is the industry standard in CF and has been demonstrated to be highly clinically predictive for CFTR modulators. We use the assay in two ways. First, we use it as an early screening tool to identify the compounds that have the most activity. Second, we use it in the clinic to determine the specific criteria or exposure targets that we needed to achieve in phase I to potentially deliver clinically meaningful benefit for patients in later-stage trials. We will share our CF HBE assay data later in this presentation. In addition to our differentiated portfolio of NBD1 compounds, we are also investing in and developing complementary modulators that target a different part of the CFTR protein and work synergistically with our NBD1 stabilizers. In dual combinations, our compounds have the potential to transform the standard of care for CF patients by bringing more patients to normal levels of CFTR function. Delving further into the importance of NBD1 on slide five, CF is caused when genetic mutations occur to the CFTR gene, impacting the CFTR protein. Within the NBD1 region is the F508del mutation. This is the most common CF genetic mutation found in approximately 90% of CF patients. F508del impedes CFTR trafficking to the cell surface and decreases the protein's overall functionality. The current standard of care is a triple combination therapy that corrects three other regions of the CFTR protein but does not directly stabilize NBD1. Therefore, the standard of care is partially correcting the mutated CFTR protein. It is our strong belief that stabilizing NBD1 is the key to fully normalizing CFTR function. We believe that NBD1 on its own can deliver substantial correction to the CFTR protein. Importantly, if we can correct just one other part of the protein in addition to NBD1, this dual combination has the potential to fully normalize CFTR function. Our goal is to develop this proprietary dual combination to provide more options and enable more CF patients to achieve normal CFTR function. Now turning to today's news on slide six. In our phase I healthy volunteer trials of our NBD1 stabilizers, SION-719 and SION-451, both therapies exceeded our desired pharmacokinetic targets and had encouraging tolerability profiles. We believe that with these compounds, we can deliver a differentiated and meaningful benefit potentially into the wild-type range of CFTR function for people living with CF. We are pleased to announce that based on the compelling phase I data, we will be advancing both 719 and 451 in a way that leverages the unique profiles of each compound to support our clinical strategy while maintaining our projected cash runway into 2028. We plan to advance SION-719 into a phase II-A proof of concept trial in CF patients, evaluating SION-719 as an add-on to the standard of care due to its potency at low doses. Based on the profile of SION-451, this NBD1 stabilizer will advance as the anchor in our proprietary dual combinations, specifically with our complementary modulators, SION-2222 and SION-109, in a phase I combination trial in healthy volunteers. We believe dual combinations are the best application for 451 due to the high exposure achieved in multiple higher-dose cohorts. While the dual combination remains our prioritized development strategy, we believe advancing both 451 and 719 to the next phase of development creates important strategic optionality. We are already making progress on these clinical plans. The IND for 719 was accepted by the FDA, and we have initiated the midazolam drug-drug interaction, or DDI, study to support the phase II-A and confirm that, as we saw in preclinical studies, 719 can be added to the standard dose of Trikafta. We expect to initiate both the phase II-A trial with 719 and the 451 phase I combination trial in the second half of 2025. Turning to our pipeline on slide seven, we have our two NBD1 stabilizers that are the anchors to our first-in-class and potentially transformative CF treatment options. As I noted, 719 will be evaluated as an add-on to the standard of care in our phase II-A trial, which will be the first NBD1 proof of concept trial in CF patients. The goal of this trial is to demonstrate that NBD1 is mechanistically unique from and synergistic with the standard of care and that CFTR function can be further improved. 451 will advance to a dual combination trial in healthy volunteers with both SION-2222, a TMD1 corrector, and SION-109, an ICL4 corrector, to evaluate the combination safety and PK of our proprietary dual combinations and inform our decision for which dual combination we will advance to a phase II-B trial in CF patients. Both our phase II-A proof of concept and our phase I dual combination trial will initiate in the second half of 2025, and importantly, data is expected in mid-2026. With our NBD1 stabilizers anchoring our robust and differentiated portfolio, we are well positioned to execute our clinical strategy and deliver meaningful and near-term data readouts. I will now turn the call over to Charlotte McKee, our Chief Medical Officer, to discuss the data and provide more details on our clinical strategy. Thanks, Mike. Now let's turn to slide nine. Our phase I clinical trials of NBD1 stabilizers SION-719 and SION-451 were double-blind, placebo-controlled trials with three-to-one randomization evaluating the safety, tolerability, and pharmacokinetic profiles of each compound in healthy volunteers. The trials were conducted in three parts: single ascending doses, or SAD; multiple ascending doses, or MAD, both of which were dosed as an oral suspension; followed by a part C that evaluated the effect of food on the PK and the bioequivalence of a tablet formulation. There were 100 total subjects dosed in the 719 trial and 110 total subjects dosed in the 451 trial. In the MAD portion of the trial, subjects were dosed for 10 days. Most doses were evaluated fasted with a few selected fed cohorts. We evaluated doses of 719 ranging from 20 mg-160 mg and doses of 451 ranging from 25 mg-300 mg, all administered twice daily. Looking at 719 first on slide 10, here are the PK data from the MAD part of the 719 trial. Orienting you to the graph, the y-axis is a log scale of mean concentration for each dose evaluated in the MAD, and on the x-axis is time in hours since the morning dose given to subjects on day 10. This was the last dose in each MAD cohort, and subjects are at steady state by this time. The colored lines indicate the mean concentration over time of the five doses evaluated, here ranging from 20 mg-160 mg. The two teal hash lines here represent the minimum target for clinically meaningful benefit based on our CF HBE assay, which corresponds to at least a 10 mmol/L improvement in sweat chloride and roughly 3 percentage points of FEV1 over the standard of care. The bottom hash line is the minimum target for 719 added to the components of Trikafta, and the top line is the minimum target in a dual combination where 719 is given with a complementary modulator. The actual concentration targets are different for these two use cases because a lower dose is required in the add-on scenario since 719 is being added on top of three modulators in Trikafta. In both cases, we're targeting the same clinically meaningful improvement above the standard of care. Our conclusion from these data is that SION-719 exceeded the exposure thresholds that indicate the potential to provide clinically meaningful benefit to patients. Every dose of 719 evaluated was above the target for add-on coverage. As Mike described, for the phase II-A proof of concept trial, we plan to focus on the lower end of our 719 dose range. These doses are all well into our add-on target concentration zone, taking advantage of 719's potency and the synergy of NBD1 with the components of Trikafta that we saw in the CFHBE assay. In part C, the tablet formulation performed well and was not meaningfully different from the suspension formulation, supporting the use of tablets in future planned studies with 719. The food effect data indicate that 719 can be dosed either fed or fasted in future planned studies. Here on slide 11, we see that SION-719 had a favorable safety and tolerability profile in the SAD, MAD, and Part C portions of the trial, consistent with our previously presented interim data. There were no serious adverse events observed, and most treatment-emergent adverse events were mild to moderate, meaning grade one or grade two in severity. There were no TEAEs leading to discontinuation of the drug and no dose-limiting TEAEs. There were no AEs related to liver function in SION-719 treated subjects and no clinically meaningful treatment-emergent trends in any other safety lab parameters, vital signs, or ECGs. Based on these phase I data, the safety and tolerability profile of SION-719 supports its advancement to the next stage of development, the planned phase II-A proof of concept trial. As we've discussed, the CFHBE assay shown here on slide 12 is a key component of Sionna's research program and illustrates the potential power of NBD1. This assay is the gold standard for the industry and, when done rigorously, has been highly predictive of clinical outcomes. Activity in this model has been shown to correlate with improved clinical CFTR function, as measured by sweat chloride levels, which in turn has been shown to correlate with improved lung function in CF clinical trials. Our research team has over a decade of experience with this model and has leveraged numerous external experts in the field over the years. Here on the y-axis is the readout for this assay, chloride current. This is a measurement of CFTR function. We've mapped the components of Trikafta at their index concentration here at the 1.0 reference point, and the dotted teal line represents the minimum target for predicted clinically meaningful improvement in this assay above that line. This is the same target I showed you in the clinical PK figures. What we see here is that in the lower range of the 719 doses we studied in phase I, we're above the minimum target in this assay for meaningful clinical benefit and potentially into the wild-type range of CFTR function when 719 is added to the standard of care. In other words, with the PK observed in phase I, we are in the target zone from the CFHBE assay of potential exposures that could deliver a differentiated and meaningful benefit with SION-719 added to the standard of care for people living with CF. Moving on to the top line data for SION-451 on slide 13, this here is the same PK data format you saw with SION-719, showing the mean concentration for each dose of SION-451 evaluated on day 10 in the MAD part of the trial. The target concentration for use in dual combination was achieved starting at the 75 mg twice daily dose, with higher doses achieving higher exposure in the dual combination target zone. These data indicate that SION-451 has the potential to provide clinically meaningful benefit in dual combination with the complementary modulators SION-109 or SION-2222, also known as galicaftor. You'll note that because SION-451 achieved higher exposure, it is higher into the dual combination target zone than SION-719, which contributed to our decision to select SION-451 to take forward into dual combination studies. Our plan is to explore the upper dose range of 451, where doses are all well into our dual combination target zone in combination with 109 and 2222 in the upcoming phase I healthy volunteer dual combination trial. Finally, similar to what we found with 719, in Part C, the 451 tablet formulation performed well and was not meaningfully different from the suspension, supporting the use of tablets in future planned studies with 451. There was no clinically meaningful effect of food, indicating that 451 can be dosed either fed or fasted in future planned trials. Moving on to slide 14, SION-451 also had a favorable safety and tolerability profile in the SAD, MAD, and Part C portions of the trial, consistent with our previously reported interim data. There were no serious adverse events, and most TEAEs were mild to moderate. There were no TEAEs that led to discontinuation of the drug and no dose-limiting AEs. As mentioned in our interim data report, we had no AEs related to liver function, with the exception of one grade one liver function test AE in a 451 treated subject in the 150 mg dose cohort who tested positive for influenza. No liver-related AEs were observed in any other dosing cohorts. As with 719, there were no clinically meaningful treatment-emergent trends in any other safety lab parameters, vital signs, or ECGs. Thus, SION-451's safety and tolerability profile, based on these phase I data, clearly supports its advancement to the next stage of development, the planned healthy volunteer dual combination study with 109 and 2222. Here on slide 15 are the 451 CFHBE assay data, again with the components of Trikafta mapped at the 1.0 reference point and the dotted teal line representing the minimum target for potentially clinically meaningful improvement. Here we see that clinical concentrations of 451 in the higher dose ranges in combination with either 109 or 2222 are above the minimum target in this assay for meaningful clinical benefit and potentially are into the wild-type range of CFTR function. In summary, based on the PK observed in phase I with 451, we are in the target zone based on this CFHBE assay of potential exposures that could deliver a differentiated and meaningful benefit with a novel dual combination for people living with CF. Now, moving on to slide 17, let's look at how we plan to advance these two NBD1 stabilizers. We look forward to the initiation of our phase II-A proof of concept add-on trial in CF patients and the phase I healthy volunteer dual combination trial in the second half of 2025. By mid-2026, we expect to announce top line data from both of these studies. We then plan to select a dual combination, our prioritized strategy for late-stage clinical development, to advance into a phase II-B dual dose ranging trial. Here on slide 18 is the high-level design for the phase II-A proof of concept study. This study will evaluate the impact on CFTR function, as measured by sweat chloride levels, of a low dose of 719 added to standard dose physician-prescribed Trikafta in patients with CF who are homozygous for the F508del mutation. This is designed to be an efficient trial. We plan to enroll fewer than 20 patients, dose for two weeks with 719 or placebo in a two-way crossover design, meaning that every patient receives both treatment assignments. With this trial, we expect to demonstrate, one, that 719 is mechanistically unique from and synergistic with the components of Trikafta; two, that there's substantial room to improve CFTR function, as measured by sweat chloride when a 719 stabilizer is added to the mechanisms of standard of care; and three, this will allow us to evaluate the translation of our preclinical CFHBE model to sweat chloride outcomes or CFTR function in CF patients. We believe positive results from this study will help validate NBD1 as a target and will also help with later dual combination clinical development, for example, supporting recruitment in the planned phase II-B dual combination dose ranging trial in patients with CF to follow the healthy volunteer dual combination trial. Now, moving to slide 19. To support advancing 719 into the phase II-A proof of concept trial, we are currently conducting a clinical midazolam DDI study to evaluate the impact of low-dose 719 on a sensitive CYP3A substrate. All of the components of Trikafta are CYP3A substrates, and ivacaftor, like midazolam, is a sensitive substrate. The goal of this study is to confirm that 719 can be used in combination with the standard dose and regimen of Trikafta according to its approved label. We have abundant supportive in vitro data, but we're conducting this clinical DDI study to confirm. The FDA has cleared the IND application for 719, and the first patient has been dosed in this DDI study. Here, on slide 20, is an outline of our planned healthy volunteer dual combination trial evaluating SION-451 in dual combination with each of our complementary modulators, again SION-109 and SION-2222 or galicaftor. This randomized, double-blind, placebo-controlled trial will assess the safety, tolerability, and PK of different doses of these two dual combinations, designed to inform our selection of the NBD1-based dual combination to advance into phase II-B dose ranging in patients with CF. Each cohort will enroll 12 subjects, randomized three-to-one active to placebo, dosed over 14 days. Our plan here is to explore the upper dose ranges of 451 in dual combination with both complementary modulators. We're on track to initiate this study in the second half of this year, with top line data anticipated in mid-2026. I'll now hand things back to Mike to discuss the unmet need in CF and the significant opportunity ahead. Thanks, Charlotte. Illustrated on slide 22, there is a large potential market opportunity for our CFTR franchise, as we are focused on the 90% of patients that have the F508del mutation. Today, approximately 2/3 of patients do not have normal CFTR function, and many other patients have tolerability issues with the approved CFTR modulators. We are confident that there is more to be done for people with CF and strongly believe that stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for CF patients. Our goal is to deliver new options for CF patients that could further improve CFTR function. Examining more closely the unmet need in people with CF on slide 23, this plot shows the results of a Cystic Fibrosis Foundation observational study of the sweat chloride for patients before taking a modulator, shown in blue, and after taking a modulator, shown in black. Each dot represents an individual patient. On the far right of this plot is Trikafta, which has demonstrated a meaningful impact on lowering sweat chloride levels, but the key takeaway here lies in the green line towards the bottom of the plot: normal sweat chloride, or less than 30 mmol/L. As we have noted, the data shows that only 1/3 of patients on standard of care Trikafta are achieving normal CFTR function. Approximately 2/3 of patients remain above that line, not reaching normal CFTR function, and that is where we believe there is an opportunity for Sionna to add value for people with CF with a differentiated NBD1-led approach. In closing, we are focused on delivering improved options for patients, and we believe we are well-positioned to do so. With our IPO last quarter, we are funded into 2028 and have the financial flexibility to execute our clinical goals. We are pioneering a first-in-class mechanism in NBD1, and the most recent phase I data for our NBD1 stabilizers has provided a unique strategic opportunity to advance both programs without impacting our expected timelines or cash runway. The compelling phase I data for SION-719 and SION-451 that we share today reinforce the potential of our novel and differentiated approach to restore CFTR function and positively disrupt the CF market. We are one step closer to our goal of transforming the treatment paradigm for CF patients, with multiple near-term catalysts on the horizon for our NBD1 programs. Lastly, I'd like to thank our dedicated team at Sionna, who has been instrumental in reaching today's milestones. We would not be in the position we are today without the dedication, commitment to excellence, and perseverance of the Sionna team. Thank you all for joining us today for this announcement, and we look forward to the discussion. I will now ask our moderator to open the call for questions. Thank you. If anyone has a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Now, first question coming from the line of Paul Matteis with Stifel. Hey, good morning. Thanks for taking my questions and congrats on all the progress you've made. Two questions just on the announcements this morning. For the Trikafta add-on study, I know you're not disclosing the dose levels, but can you just walk us through the thought process on dose selection? I guess I understand you want to prioritize a low dose, but how conservative are you being in your minds as it relates to giving yourself some margin, right, and some comfort that you can meet or exceed this 10 mmol bar? Two, on 719, maybe just talk about the preclinical work you did and your confidence, right, that that's predictive of there not being a drug-drug interaction. If I could just slip one more in on 451, understanding the dose levels are higher, would there have been a concern to run the Trikafta add-on study? I guess there is a feeling that the 719 data are just leverageable to 451, and I guess that is not necessary, but any more color there would be great. Thank you. Yeah, Paul, thank you for the questions. We'll rattle through them. I'll let Charlotte take the first two or three, and then I'll take the last one on 451. Yeah, so I may need some refreshing on what they are, but thanks, Paul. Your first question is about the phase II-A add-on dose of 719. We're very confident in the dose range that we'll be exploring for that phase II-A study, as we've seen on the PK curve, and as we've described, every single dose of 719 is well into the add-on concentration target zone. We think we're in a really good predicted zone in terms of activity for that study. As we've described, the sort of sequence will be we will confirm with the midazolam DDI study that we're in the green zone with respect to the components of Trikafta. I think you mentioned the questions about the in vitro data. These are pretty standard in vitro assays that just look at the potential for drug-drug interactions at different doses, and those look very, very clear to us from the in vitro data. As I mentioned, we just are doing the clinical study simply to confirm, but we've got a very nice zone of target doses that we're very happy with. Yep. I'll add to the 451 question, Paul. Your question was, why not take both, really, 451 into the add-on like we did with 719? If you step back in what we announced today, what we really are talking about is leveraging the unique profiles of each compound, right? We're going to take 719 as the add-on on top of Trikafta, the standard of care in that phase II-A proof of concept study, and then 451 will be the anchor to the proprietary dual combination work that we will do. It's really based on their profiles. What you heard us talk about was 719's potency at those lower doses was meaningfully different than 451 and looks like the best option to support that proof of concept study. With 451, the higher exposures achieved at the higher doses was really differentiating and looks like the best option for the dual combination. If you step back to your question, Paul, what we're trying to do with that phase II-A and taking 719, it is really a proof of mechanism, right? A proof of biology of NBD1. Because of the profile of 719 being the best to support that study, that's the strategy we chose. It will be very transferable to the dual combination work that we will do because what we're showing is that NBD1 is unique and differentiated from the components of Trikafta, that there's more CFTR function to deliver here with an NBD1 stabilizer. This will also be our first chance to show the translation of the CFHBE assay in CF patients. Even with 719, that is translatable to 451. We're very confident in this strategy that even though they are separate parallel paths, they are very complementary to the work we're trying to do on the development side. Awesome. All right. Thanks for all the color. Appreciate it. Yeah, thanks, Paul. Thank you. Our next question coming from the line of Yatin Suneja with Guggenheim. Your line is open. Hey, guys. Thank you for taking my questions and congrats on the nice presentation and the data. Two for me. One is, I think Mike was trying to allude to that. The question is, if you can maybe describe to us the kinetic differences between these two molecules, because if you look at 719, faster kinetics, but obviously 451 gets you higher exposure. How does that fit into your thinking? One. Do we know the doses that you are taking forward in the add-on study or in the future studies? Finally, I think in the past you have said that dual combo is your go-to or your preferred strategy, but why not also take add-on or be open to the add-on strategy as well if you can just articulate on that? Thank you. Yeah. Thanks, Yatin. Yeah. So, Charlotte, do you want to take the first two, and I'll take the last one? Yeah. So really, yes, and as you and others have seen from the PK slides, our dosing optimization was really about where we are in the target concentration zones, again, based on our CFHBE assay predictions. You're right, there are slightly different kinetics. That does play into the potency, for example, of 719 and the higher exposures of 451. Really, we were laser-focused on where we are in the target zone. In the lower zones, because of 719's potency, it really was kind of a no-brainer, frankly, to focus on that for the add-on. Similarly, it was really the target coverage based on the higher exposure for 451 that, again, was just pretty obvious to us as we sort of stepped back and looked at all the data. Fortunately, we didn't have to make any sort of differentiation based on safety or tolerability data, which gave us the luxury of being able to really focus on the target coverage and the target zones for both of these. As far as the dose levels, that is, we're looking in the ranges that you've seen. And as you can expect, we're not describing the actual doses. Yeah, really for competitive reasons, Yatin, right? We feel very confident, as Charlotte said, in the lower dose range, as you saw on the HBE curve. We're well above that target that we had, the meaningful target that we set, but also potentially into wild types. We feel very confident about even at the lower doses, this could be very meaningful. On your last question, you'd asked about the dual combination and the add-on, would we ever commercialize both of those? You did hit it initially. Our prioritized path, as we have consistently said, is the dual combination. The proprietary dual is ultimately what we think creates the highest level of differentiation and what we think is the best option for patients. Having said that, both of those paths are commercially viable. The add-on and the dual combination are viable commercial paths. By making the strategic decision we did today, by putting 719 as the add-on and 451 as the dual combination, it really creates that meaningful strategic optionality that keeps those choices or those options in play. We will always be data-driven in terms of what path we will choose. As of today, we continue to reinforce the prioritized path is dual combination. That is not to say that with data that we have multiple options to progress in the future. Thank you. Our next question is coming from the line of Ritu Baral with TD Cowen. Your line is now open. Hi, guys. Thanks for taking the question. You mentioned the DDI midazolam study for 719, but there was no mention of future DDI investigation for 451. Are there any DDI studies that are gating for the start of the 451 healthy volunteer combination, that dual combination? The follow-up to that is, as you look at that trial, that trial design, sort of what are the swing factors that you're going to be most focused on deciding between galicaftor and 109 to put together with 451? Yeah. Charlotte, do you want to take that? Yeah. Thanks, Ritu. No, for 451, your question was, are there any other studies, frankly, any other studies gating for the healthy volunteer dual combination study? The answer is no. All the data are in. We're moving forward with preparing that. Because we're combining our own two drugs in combination in the healthy volunteer, in that healthy volunteer dual study, that just gives us a lot of flexibility. We're not, unlike in the add-on to standard of care study, we're not beholden to any specific profile of a background or add-on therapy. Of course, as we progress, if we're progressing into later combination studies in full development with 451, there's a whole suite of clinical pharmacology studies that we will plan to conduct with 451 and a complementary modulator, but we don't have to do that before the healthy volunteer studies. Your other question is about what factors we'll be looking for in the dual combination healthy volunteer studies. It really, as we've described, the goals of that study are safety, tolerability, and PK. We'll be looking at basically the same criteria that we really evaluated deeply in the prior portions of the phase I study, the SAD and the MAD portions, really how the safety and tolerability allow us to move as high into our target zones as possible with both of these complementary, with both of the modulators in combination and the safety and tolerability. Yeah. And just maybe to piggyback off that, Ritu, we are, as you probably know from the past, we've been very focused, as Charlotte said, on the efficacy, right? We have to see how these combinations come together in that healthy volunteer study to look at the PK and the tolerability profiles. All things being equal, efficacy is a major driver for us in terms of how we would select. We want to create the best and most differentiated options for CF patients that we can, with efficacy being the main driver. Got it. If I could squeeze one last in, in the liver, the LFT-TEAE, how far above normal did that particular event go? Yeah, that was a mild liver function test, a grade one in the setting of active influenza. So a very mild elevation. We should be thinking like 3x upper limit of normal or something like that? The grade one zone goes up to 3x the upper limit of normal. It was in that lower zone. Understood. Thank you. Thank you. Our next question coming from the line of Salveen Richter with Goldman Sachs, your line is now open. Hi, this is Charlotte on for Salveen. Congratulations on the data. Can you help us understand the clinical meaningfulness of the PK thresholds that both the assets hit, particularly in terms of the benefit over standard of care that is expected? Yes. Hi. I'll take that first. The minimum bar that we've set, again, based on the CFHBE assay, corresponds to a minimum bar of, as we've described, at least 10 mmol/L of sweat chloride differentiation, which has also generally corresponded to roughly a 3 percentage point of FEV1. That across really all the development of the CFTR modulators and talking to thought leaders and based on the history of CF and how it progresses, that is a pretty consistently consensus-driven bar to correlate back to a clinically meaningful endpoint and improvement, both in CFTR function and in lung function. Great. Thank you. Thank you. Our next question coming from the line of Liisa Bayko with Evercore ISI, your line is now open. Hi. Thanks for taking the question. As you look forward into future development, any plans to combine any of these molecules with Trikafta and anything that would prohibit that from a sort of an interactive perspective? Thank you. Yeah. Hi, Liisa. Our current paradigm, because as Mike described, the add-on to standard of care for now in the development program really is proof of mechanism, proof of concept, proof of biology, however you want to describe it. Because the mechanisms in both of those triples, Trikafta and Alyftrek, are the same, we don't think that it's necessary to do proof of concept, proof of mechanism trials on every single one of them. From a mechanistic perspective, adding NBD1 to Trikafta is very—it's the same mechanistic, answering the same mechanistic questions as it would be adding to Alyftrek. We liked using a standard of care that has been out there for a while where the uptake is higher, and there's just a much better-known background in terms of our phase II-A study. Now, if we were to go forward into a full commercialization path on top of the standard of care, we'd obviously be just taking into account what the overall uptake is and what patients are actually on. Mechanistically, and actually, as you know, even in terms of efficacy and other outcomes, both of those are extremely similar. No immediate plans, but as Mike says, we'll always be data-driven. If plans in the future evolve with a whole add-on scenario, we'll explore. Okay. Great. Thanks.