Good afternoon, and welcome to the Sionna Therapeutics conference call. At this time, all participants are in listen only mode. After today's presentation, there will be an opportunity to ask questions. To enter the queue, please 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. Juliet, you may begin. Thank you. Good afternoon, and welcome to today's conference call. Joining me are Mike Cloonan, our President and Chief Executive Officer, and Charlotte McKee, our Chief Medical Officer. Elena Ridloff, our Chief Financial Officer, will also join us for the Q&A session. Following our prepared remarks, we will open the call for 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 and 8-K filed with the SEC, as well as any subsequent SEC filings. 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. Thanks, Juliet, and good afternoon, everyone. Thank you for joining us. Today, we are discussing two important updates, the findings from our comprehensive post hoc analysis of the PreciSION CF Phase IIa trial following top-line results announced in August, and how these findings informed our decision to advance SION-451 plus SION-2222 into the next stage of development. Our conviction in NBD1 stabilization remains strong. The post hoc analysis deepens our understanding of the NBD1 biology and target engagement and identified important trial learnings, giving us a clear and disciplined path forward. Several findings were particularly important. First, we identified three participants with PK patterns consistent with dosing non-adherence that disproportionately affected the original result. Excluding those participants, the mean placebo-adjusted reduction in sweat chloride was up to 8.6 mmol per liter, which we believe is consistent with NBD1 biological activity and target engagement. Second, even after adjusting for those participants, we identified two factors specific to the four-drug combination of SION-719 plus Trikafta that may have blunted the observed effect. Lower exposures of the Trikafta components during the SION-719 treatment period and a possible biological interaction with the potentiator Trikafta, ivacaftor. Together, these findings may help explain why SION-719 did not demonstrate its potential when added to Trikafta, and why we believe our NBD1-anchored dual combination without Trikafta or a potentiator could behave differently. Combined with the favorable phase I safety, tolerability, and PK results for SION-451 plus SION-2222, we believe the post hoc analysis supports advancing the dual combination into AscenSION CF, an open-label phase IIa proof-of-concept trial expected to initiate in the first quarter of 2027. We are focusing our organization and capital on that dual combination program. This includes the difficult decision to reduce our workforce by 46% and other cost-saving actions, which are expected to extend our cash runway into the second half of 2029 and to support execution of the dual combination strategy. Before moving forward, I want to recognize the Sionna colleagues who will be leaving the company as part of this restructuring. We are deeply grateful for your dedication, resilience, and contributions to our mission. I also would like to thank the CF community for the outreach over the last several weeks that has provided inspiration to our team and a strong reminder of the unmet need that remains for people living with CF. With that, I will turn the call over to Charlotte to walk through the analysis supporting our decision and our go-forward plan. Thank you, Mike. As a reminder, PreciSION CF was a randomized, double-blind, placebo-controlled, two-way crossover trial evaluating 30 mg of SION-719 twice daily when added to physician-prescribed Trikafta in adults with CF homozygous for F508del. After screening and a 14-day Trikafta run-in, participants received 14 days of SION-719 plus Trikafta and 14 days of placebo plus Trikafta in a randomized order with a 28-day SION-719 washout between treatment periods. 14 participants completed both periods. The primary endpoint was safety and tolerability, which we described when we announced the top-line data. Secondary endpoints included pharmacokinetics and change in sweat chloride, an important biomarker of CFTR function. Two sweat chloride analyses were pre-specified in our protocol. The primary analysis was change in sweat chloride from study day one, and the secondary analysis was change in sweat chloride from the baseline of each treatment period. We believe the secondary analysis using the baseline of each treatment period is most appropriate for this data set, given the PK and sweat chloride variability we observed. Turning to slide six, following announcement of the top-line data in August, we conducted a thorough, disciplined post hoc review of the trial, as Mike mentioned. We evaluated multiple dimensions of the data, including PK and sweat chloride patterns in individual participants and in subsets. The potential impact of baseline and other characteristics and exposure response analyses. There are three factors we believe provide a reasonable and consistent interpretation of the data and potential confounders that may have impacted the results. Three participants had patterns of drug levels and sweat chloride values at key study time points that were consistent with dosing non-adherence, and we believe confounded the trial outcome. When we adjust for those participants, we see what we believe is evidence of target engagement and NBD1 activity, albeit still at a lower level than what we predicted. Second, we saw consistently lower levels of all three components of Trikafta at the end of SION-719 treatment periods. The goal of this trial was to evaluate SION-719 on top of stable Trikafta levels, and this is not what consistently happened. While the implications are not completely clear, this finding suggests that lower Trikafta exposures may have reduced the impact of NBD1 stabilization. Finally, we have reviewed the non-clinical data in light of the trial outcome, which led us to an emerging hypothesis that combining SION-719 with Trikafta, and specifically with a potentiator, may have unexpectedly blunted the ability to improve CFTR function further with an NBD1 stabilizer. Slide seven shows waterfall plots of individual participant-level sweat chloride changes for all 14 participants, calculated from each treatment period baseline. On the left is the SION-719 period, the placebo period is in the middle, and placebo-adjusted changes are shown on the right. The three outlier participant sweat chloride changes are shown here in the gray bars. On slide eight are more details about these three participants. Two had unmeasurable or unusually low levels of the components of Trikafta at the start of the placebo period after the SION-719 washout, and expected levels of Trikafta at the end of the placebo period, with very large improvements in sweat chloride over this period. We believe these participants' placebo effects were consistent with non-adherence with dosing at the beginning and confounded the trial results. A third participant had unmeasurable SION-719 levels at the end of the SION-719 period, which was inconsistent with levels from the other participants and from healthy subjects given the same range of doses, and we believe this participant's data further confounded the trial outcome. Importantly, we did not identify similar confounding patterns in any other participants. When we removed these three PK outlier participants in a post hoc analysis, shown here on slide nine, we saw what we believe are consistent patterns in the data that indicate target engagement and NBD1 stabilization. During the SION-719 period here on the left, most participants had a numerical reduction in sweat chloride, while during the placebo period in the middle, sweat chloride changes appear very balanced, as you would expect. In this post hoc analysis, the placebo-adjusted changes also trend towards an improvement in sweat chloride. We further probed this post hoc sensitivity analysis using the model specified in the trial, MMRM, or mixed model for repeated measures, shown here on slide 10. The dark blue bars represent this pre-specified sweat chloride analysis in all 14 participants. The primary result, as we reported in August, was a mean change of -1 mmol per liter. In the pre-specified secondary analysis, using each treatment period as its own baseline, the mean change was essentially the same, -1.1 mmol per liter. The teal bars represent post hoc analyses showing the impact of removing the three participants with outlying PK. The top teal bar shows the result using study day one as baseline, a mean sweat chloride reduction of 3.8 mmol per liter. The bottom teal bar shows the result using each treatment period's baseline, which we believe best accounts for observed variability, a mean reduction of 8.6 mmol per liter. We believe that this post hoc analysis provides a less confounded view of the data and shows evidence of biological activity from NBD1 stabilization. On slide 11, we show that the mean trough, or pre-dose exposures of all three components of Trikafta, or ETI, declined on average over the course of the SION-719 period, while ETI levels were generally stable on average during the placebo period. We mentioned this observation when we first reported the data. The dark blue bars represent the mean changes in ETI levels from left to right, elexacaftor, tezacaftor, and ivacaftor in the placebo period, and the teal bars represent mean change in ETI levels over the SION-719 period. The three PK outlier participants are not included. As you can see, ETI concentrations remained relatively stable on average during the placebo period, while they declined by approximately 25%-30% on average over the SION-719 period. While we could not quantify the potential impact of this finding, this is not what we intended or expected when we designed the trial, and we believe it's possible that lower exposures of some or all of these components could have reduced the incremental effect of adding NBD1. Importantly, this specific four-drug complexity will not be a factor when SION-451 plus SION-2222 is studied as a standalone dual combination. Before we describe our emerging biological hypothesis, here on slide 12 is a brief refresher on CFTR and CFTR modulators. CFTR is a multi-domain protein. The most common mutation, F508del, resides in the NBD1 region and creates multiple defects in protein processing, trafficking, and function. A robust set of scientific literature supports the importance of NBD1 for proper CFTR folding, trafficking, and functioning, and none of the approved modulators directly binds and stabilizes NBD1. Approved modulators include correctors and potentiators. Correctors generally address CFTR folding, processing, and trafficking, and potentiators are designed to open CFTR at the cell surface. In Trikafta, tezacaftor is a TMD1-directed corrector, elexacaftor is an ICL4-directed corrector, and ivacaftor is a potentiator. Prior to the PreciSION CF results, our guiding hypothesis was straightforward. Based on what had been observed with approved modulators to date, all our non-clinical data, shown here on slide 13, demonstrated that adding NBD1 to Trikafta should improve CFTR function. Data with NBD1 in dual combination across all our non-clinical assays are shown here on the right. After the unexpected clinical results, we conducted a thorough review of all of our non-clinical data to inform the path forward. One emerging hypothesis relates to high levels of pre-stimulated current in the CFHBE assay when NBD1 is added to Trikafta. We had expected the totality of the non-clinical data to be associated with increased CFTR function based on correlation with the approved modulators. However, this one component across our non-clinical data differs from the wild-type pattern when SION-719 is added to Trikafta, and the dual combination in this case is similar to wild type. What PreciSION CF may have taught us is that creating a high level of pre-stimulation current may lead to dysregulation of CFTR and might have limited the ability to improve CFTR function when SION-719 was added to Trikafta. I'll walk through the CFHBE assay data that led us to this working hypothesis, beginning here on slide 14. These are representative tracings from human bronchial epithelial cells, or HBEs, from a wild-type, normal donor on the left, and from a CF donor homozygous for F508del on the right. The x-axis shows time and experimental conditions. The y-axis shows chloride current, or CFTR activity. In the wild-type donor on the left, CFTR activity is low before stimulation. The channels are activated with stimulation, and we see a sharp increase in current. Current then plateaus until CFTR is inhibited. This is a normal tracing in the CF-HBE model. The gray tracing on the right shows what untreated F508del CFTR looks like, basically flat throughout. The magenta tracing shows the response to ETI, the components of Trikafta, which has demonstrated clinical activity here at maximum exposures, or Emax. There is some activity before stimulation, consistent with some open CFTR channels, an increase with stimulation, plateau, and a fall with inhibition. In this model in general, the level of CFTR activity observed with the components of Trikafta is lower than wild-type activity. Here on slide 15, the turquoise tracing shows SION-719 when added to ETI at SION-719's Emax. There is more activity before stimulation and a larger peak and plateau response. This pre-stimulation current increases with increasing concentrations of SION-719. For example, pre-stimulated current with a 30 mg concentration of SION-719 is about half what is shown here at SION-719 Emax. We consistently see higher levels of pre-stimulation current when a potentiator is present in any of our NBD1 combinations, but not in combinations without a potentiator, consistent with the known mechanism of a potentiator opening CFTR channels. What the clinical data may have shown us is that this CFTR behavior when NBD1 was added to ETI may have led to dysregulation of the CFTR channel that blunted the driving force of chloride ion flow, limiting the ability to achieve the expected improvement in CFTR function with SION-719. This remains a working hypothesis, but we believe this provides a plausible biological explanation for why the clinical results were different from what we predicted. This hypothesis has important potential implications for our dual combination, which does not contain a potentiator. The blue tracing here on slide 16 shows SION-451 plus SION-2222 at Emax in this model, with the CFTR channel here behaving more like wild type. Based on this emerging hypothesis, these data suggest that the dual combination may modulate CFTR in a more physiologic way than when SION-719 was added to Trikafta. Taken together, our post-trial findings reinforce our view that PreciSION CF does not provide a definitive read-through to NBD1 biology. They also strengthen the rationale for evaluating SION-451 plus SION-2222 directly in the proof of concept AscenSION CF trial, without the added complexity of combining with Trikafta or a potentiator. I will now turn to our next steps for the SION-451 dual combination program. Before we discuss our plans for advancing the dual combination, I want to reemphasize the clear need for additional treatment options. Current CFTR modulators have transformed care, but more than 2/3 of patients on today's triple combination standard of care do not reach normal CFTR function as measured by sweat chloride, and many continue to experience incomplete clinical benefit or tolerability challenges, and their alternatives are very limited. We continue to hear this desire for options directly from the CF community, even in the weeks since we announced the clinical results. Slide 19 is a reminder of the outcome of the phase I trial of SION-451 in combination with the TMD1 corrector SION-2222 and the ICL4 corrector SION-109. A total of 120 healthy subjects were dosed for 14 days across 10 cohorts, divided evenly between the two combinations. We identified combinations of both SION-451 plus SION-2222 and SION-451 plus SION-109 that were generally well-tolerated and exceeded our PK targets at go-forward doses. Based on the totality of the data and the level of target coverage achieved, we selected SION-451 plus SION-2222 as our preferred dual combination. The exposures of both drugs were similar to what we observed when each was studied alone. Slide 20 is a reminder of the safety and tolerability profile of this combination. We selected SION-451 twice a day and SION-2222 once a day as the preferred regimen. All SION-451 cohorts with SION-2222 dosed once daily were generally well-tolerated, with all treatment adverse events mild to moderate in severity. There were no serious adverse events and no treatment-emergent events related to elevated liver function tests. One participant discontinued dosing due to a moderate rash. Turning to slide 21, we are excited to advance this proprietary dual combination into the AscenSION CF phase IIa proof-of-concept trial, an open-label study in adults with CF homozygous for the F508del mutation. Participants will switch from Trikafta to the dual combination for 28 days. The study will assess sweat chloride, safety and tolerability, and PK to evaluate preliminary clinical efficacy and safety data with the dual combination in people with CF. We will be incorporating lessons from the PreciSION CF trial, particularly in relation to dosing adherence, sweat chloride variability, and PK monitoring. We plan to start AscenSION CF in the first quarter of 2027. Personally, I consider it a tremendous privilege and responsibility to evaluate the first NBD1-containing dual combination in people with CF, with the goal to create meaningful options for patients. I know from experience how life-changing transformative medicines can be in CF, and I am committed, with the dedicated team here at Sionna, to probing the full potential of this novel mechanism. With that, I'll turn the call back to Mike for closing remarks. Thanks, Charlotte. Turning to slide 22, the post-hoc analysis Charlotte presented explains why we believe the dual combination may behave differently. SION-451 plus SION-2222 represents a potentially differentiated profile for people living with CF. Our objective now is to determine whether this combination can deliver meaningful CFTR benefit and provide an alternative to today's triple regimen standard of care. The favorable phase I tolerability and PK results provide the foundation to answer that question directly in people with CF. AscenSION CF is designed to be an efficient proof-of-concept study that will evaluate preliminary efficacy and safety and help define the potential clinical profile of the combination. If successful, that profile could create significant value in an approximately $13 billion market, and more importantly, provide an additional option for people with CF. We are now moving from analysis to execution with a focused development plan and the financial resources to reach important phase II milestones. As the only company advancing an NBD1 stabilizer in clinical trials, we remain committed to pursuing this opportunity with scientific rigor and urgency. We expect to initiate AscenSION CF in the first quarter of 2027. I want to thank the participants in our clinical trials and their families, our investigators and site teams, the Cystic Fibrosis Foundation and our advisors, our shareholders, and the entire Sionna team. We are committed to making a difference in the lives of people living with CF and their families, and we believe moving forward with the dual combination of SION-451 plus SION- 2222 is clear evidence of our commitment to the CF community while we continue to follow the science. Thank you all for joining us today. I will now ask the operator to open the call for questions. Thank you. If you have a question at this time, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In the interest of time, we ask that you limit yourself to one question. One moment for our first question. Our first question will come from the line, Ritu Baral from TD Cowen. Your line is open. Hi, guys. Thanks for taking the question. I wanted to just go back a few slides and make sure I understood the hypothesis on the components of the CFTR. I think if I got this right, you believe that the binding at the NBD1, together with the binding of the one subunit, results in some sort of inhibition. I am sorry, the potentiator results in inhibition. Is that the result of some sort of spatial obstruction of the CFTR channel by the TMD2 and the NBD1 interaction? Is it potentially chemical or charge-based? What made you think of the potentiator as the driver of this interaction rather than something about TMD1 that could potentially impact SION-2222? Hi, Ritu. I will start. This is Charlotte. Across all of our data, we see no evidence that there is some sort of steric or binding interference between SION-719 or the NBD1 stabilizers in any of the components of Trikafta, so we do not believe that this is a binding interference. The pre-stimulation current that we described, and we do understand this is a complex biological hypothesis, so appreciate you bearing with walking through it with us. That pre-stimulation current is actually consistent with what a potentiator does, which is open channels. That is why the hypothesis that this is related to combining with a potentiator makes sense to us. It is really, if you think about it, an analogy is the water flow or force of water flow on either side of a dam. The voltage and the current that the cell needs to maintain in order to drive ions through the CFTR channel is really just like that dam. What this increased pre-stimulation current may represent is basically a blunting of the difference in the levels of the voltage and the current along this, analogous to the different levels of water on either side of a dam that limits the ability to generate the kind of driving force that you would need. Yeah, Ritu, maybe just to ask too about the potentiator was how do you know it is the potentiator and not TMD1 or ICL4? We didn't show it in those slides today, but we have run the same model with SION-719 over SION-451 when we added just elexacaftor and tezacaftor, so not with ivacaftor, not with the potentiator, and we don't see that same level of pre-stimulation of the current. Then you clearly see when you add SION-719 or SION-451, any NBD1 stabilizer to ETI, we see this distinct difference when the potentiator is in play, not when it isn't. Got it. Thank you. Thank you. One moment for our next question. Our next question will come from the line of Chris Raymond from Raymond James. Your line is open. Thanks, and congrats on turning this around so fast. I guess just a question on AscenSION, and I know it's early here, but this is not the same thing as the initial look, so I would suspect a 10 mmol reduction is not sort of a bar for success. But how are you thinking about? Is it just non-inferiority to baseline? Because it's a simple switch. There's no washout, right? I guess that, and also what patient compliance with a trial like this, I guess it's a little bit of a surprise. Just maybe what specific learnings you are incorporating into AscenSION to make sure you have adherence. Thanks. Yeah. Hi, Chris. This is Charlotte. I'll start with the second one. Some of the specific learnings we have taken away with respect to adherence include variability. What we'll specifically be thinking about with respect to AscenSION CF is, one, both statistical and other ways to reduce the variability that some of these PK and other changes really represented. We will be looking, as you pointed out, we'll be looking at all sorts of ways to help both the trial sites and the patients maintain strict adherence to the extent that does appear to have been a confounder, maybe added to the variability. Maybe just on that, Chris, on the compliance or non-adherence. Two of those participants that we talked about were on Trikafta, and that was not a study drug, right? We were not controlling for the Trikafta part. Only one of the patients was a SION-719 that looked like they had non-adherence. The adherence is also important when it happens, right? Because of when we were measuring sweat chloride in this study. If it happens later, at that time, it may have more of an impact. This was a small study, and unfortunately, a couple of patients can make a difference. So that's an important thing here to learn as we apply that to AscenSION. Now we can switch to the first question. I've forgotten the first question. That was about how we measure- The bar for success -sweat chloride at the medical act baseline. Right. The vision is, this will be 28 days of dosing. The vision is to look at the change from baseline. There, of course, everything we were just talking about in terms of variability and assessing the baseline becomes really important. We will be looking for mechanisms and statistical ways to ensure that that is as tight as possible. Then over the course of 28 days, any of the PK of, for example, residual Trikafta should be long gone. Our intention then would be that the readout in sweat chloride, for example, at the end of that 28 days would represent the impact of the dual combination. Thanks. Thank you. Our next question comes from the line of Paul Matteis from Stifel. Your line is open. Hey, thanks so much for taking my questions. I appreciate it. On the lower Trikafta exposures, can you talk about how variable that was across patients? Is there any analysis you can do that looks at whether or not lower Trikafta exposures are inversely correlated to activity? Then second, I just wanted to clarify this whole dynamic with the primary endpoint and the secondary endpoint. Obviously, the eight number you are getting to, or 8.5, is on this secondary endpoint for analyzing sweat chloride. Maybe go back. Why was the primary endpoint structured as it was? That is showing less than four, which is considerably less. Why is the four or three to four number not the right number to focus on? Why should we be focused on the 8.5? Thank you. I will do the second one first, Charlotte. Yeah. Thanks, Paul. I'll let you start. The analyses and again, this is a sort of statistical complexity, but in a two-way crossover. The expectation in a two-way crossover is that in the baseline and whatever the value is at baseline across those two different periods, basically remains the same or very stable. And we did see as we've said, there was simply more variability from the two baselines over the course of even the Trikafta only measurement points across the study. And there seems to be some emerging data after we had powered and designed the study, indicating that some of those, both Trikafta PK and some of those sweat chlorides maybe weren't more variable than the data we had at the time may indicate. It's really just a two-way crossover study design thing, is that the clearest and the most sort of the purest analysis is you take the day one steady baseline because you're expecting everything to be the same at baseline going across the trial. But since we did not see that the two baselines were different, even though nothing else was different about what the patient should have been on or were taking, that is why using each treatment period as its own baseline, especially in this post-hoc situation, we believe best represents the data. We really, when we talk about those specific numbers in that post-hoc analysis, we really think of them more as a range, and we're not trying to identify what the precise, no pun intended, outcome of the study is. What we really have been interrogating is, do we see any evidence that there was a biological impact? And that range of frankly roughly four to north of eight tells us that it was likely to have been some biological impact of modulating NBD1 and also the different patterns that we see in the waterfall plot give us the same sense. Yeah, that was the first thing we had to address, Paul, going deep. We really needed it for ourselves to see that there was some target engagement in NBD1 biology activity here, and that's why those two measures for us were important to see whether it's the - 4 or the - 9. As Charlotte said, we do tend to think, given the results of this study and what we saw from both the PK variability and sweat chloride variability, the secondary analysis may be more representative, even though we designed the study to go all the way back to day one. So that was really important for us to first answer that question around NBD1 target engagement. And then your other question was related to the ETI concentration. That's where we went next, which is, okay, we saw evidence of NBD1 biology and target engagement, but it was not to the level. Whatever number you use, it's not to the level we were expecting. It was still lower. What else could be driving this? When we have such strong conviction in the NBD1 biology, that's where the ETI concentrations came into play. What we saw consistently, as Charlotte outlined, when you look at the placebo, on average, they basically stayed pretty consistent over that period of time. When they were on Trikafta plus SION-719, on average, they saw a drop of 25%- 30% across ETI. The challenge we had is, as you probably remember, we didn't have very robust PK information. This was trough level data, so it was really hard to correlate back to model it. Again, with only 11 patients, once you took out the outliers, to get at a quantification of what that concentration would mean in terms of sweat chloride. But one of the hypotheses was that if we are bringing down sweat chloride with NBD1, but there's upward pressure because ETI's concentrations are not where they were before, there's a counterbalancing there or a reduction potentially in NBD1. Again, we couldn't quantify it specifically, but we obviously observed that pattern with ETI. As Charlotte said, that's not what we thought we were going to get in this study. We thought patients would be stable throughout on Trikafta. There's normal variability, but there was a very different pattern between placebo and Trikafta and SION-719 and Trikafta. Thank you. One moment for our next question. Our next question will come from Yatin Suneja from Guggenheim Securities. Your line is open. Hi, everyone. Thank you for taking my question. Just two quick ones. Number one, I understand this is shorter duration, but were you able to look at the FEV1 lung function for these patients at all? Anything that you can share around that? Then specifically with regard to the two patients that have a pretty robust change in sweat chloride level, any additional information you are able to share? Anything about their baseline sweat chloride level and sensitivity to the add-on? Thanks. Yes. Hi, Yatin. This is Charlotte. I will take that. We did not see any trends in FEV1. As you know, we said from the beginning, this was a two-week study, so we were not really expecting to see anything in FEV1, and especially, with this kind of lower than expected effect in this range, we did not see anything. I would say the two patients with the placebo, what we believe are confounded placebo effects, there was nothing different specifically about their baseline characteristics. Really what we described were the key findings, and it really was that post-washout start of the placebo levels of Trikafta that were really strikingly low. Then not just for the group, but for these participants specifically. Then at the end of the placebo period, those levels came right back up to where they had been for these participants at the start of the trial. Thank you. One moment for our next question. Our next question will come from the line of Salveen Richter from Goldman Sachs. Your line is open. Hi, this is Lydia on for Salveen. Thanks so much for taking our questions. Maybe just to follow up on a prior question, have the three potentially confounded patients actually been confirmed to have not adhered to dosing? Also, given that AscenSION is going to be a simple switch, are there any clinical risks associated with withdrawing from Trikafta that could potentially impact the efficacy results? Thanks so much. Yeah. Hi, Charlotte again. I will take both of these, at least to the start. So we did a lighter sort of adherence check in the study, and as Mike noted, Trikafta was not a study drug per se, so our ability to really zero in on and do drug accountability, et cetera, was quite limited for the Trikafta period, or the Trikafta components. So that is a lesson that we will be taking forward with the dual combination. With respect to the simple switch, we know what the elimination half-lives and PK of Trikafta are. So over a 28-day period, those components should be long gone by the end of the 28-day period. Thank you. Our next question will come from the line of Jon Wolleben from Citizens. Your line is open. Hey, thanks for taking the question. I am wondering about dosing moving forward. Do you have one dosing regimen for the combo to move forward, or are you going to be testing a range? When you mentioned in the release that the planned doses were in produced meaningful improvement in CFTR function, can you talk a little bit more about what you actually saw in the assay at these doses? Thanks. With respect to the study design and the dosing for the AscenSION study, we are in the midst of finalizing that study design. We will be providing more details as we start the study, across dose regimen, et cetera, and the whole study design. Yeah, Jon, on your question about the assay translation. If you go back to what we had said, we had set, as you know, very specific PK targets going into the phase I dual combination study, and we exceeded those with SION-451 and SION-2222. It put us in a good position. We have been consistent with our dual combination that we have always said this is our prioritized path. We think this has the opportunity to create a really differentiated profile. The way we have always thought about the dual combination is from a target product profile, it is looking for superiority. From a minimum product profile, it is equivalency, right? But always looking at that tolerability as well, profile is how that can differentiate. So that continues to be the case, and we're moving forward with dual because we feel confident and feel good about what that profile has the potential to be based on the PK and the totality of the PK plus safety and tolerability profiles. Thank you. Our next question will come from the line of Brian Abrahams from RBC Capital Markets. Your line is open. Hey, guys. Thanks so much for taking our question. I wonder if you could talk about the type of patients you expect might enroll in the AscenSION study as compared to the SION-719 study. Do you think this might select for certain patients who are willing to go off of Trikafta? And how do you sort of manage that through inclusion, exclusion criteria? And then any sense of what the size of the study could be or the potential enrollment timeline goals for that study? Thanks. Yeah. Hi, Brian. Charlotte again. I'll take those. As far as the size and the kind of design of the study, as I said, when we start the study, we'll provide more details on the study design, et cetera. So those are in process at this point. I do think we are hearing from the CF community as we mentioned earlier, loud and clear and actually, really that drumbeat and those calls did not diminish after we announced the results of the SION-719 study. We're hearing that patients and the community really, really are interested in alternatives. So our expectation is that, we will obviously have eligibility criteria that will be appropriate. But our expectation, based on what we're hearing from the community, is that there is a very strong desire for alternatives. We do not expect this to be only the patients who would not otherwise be on Trikafta. We expect this to be a test of what stable Trikafta versus our dual combination looks like. Your question, Brian, around the size. As Charlotte said, we are finalizing the protocol. We will give more details once that is available to us and that is finalized. The guidance we are giving on timelines right now is the initiation. We expect to initiate in the first quarter of 2027. Expect more information as we finalize the protocol, but that is what we are giving out today. Got it. Look forward to that. Thanks, Mike. Thanks, Charlotte. Thank you. Our next question will come from the line of Kambiz Yazdi from BTIG. Your line is open. Thank you for the update. Why do you think pre-stimulation activity is so critical for CFTR function? Did you also happen to look at the pre-stimulation activity of the dual combination you are not moving forward with, SION-451 plus SION-109? Thank you. Yeah. I will start with that. This hypothesis about the pre-stimulation current is just that. It is a working hypothesis. As we mentioned earlier, that is the one component of the preclinical data that is different with the add-on SION-719 to Trikafta from specifically the dual combination. There is a plausible hypothesis that this current may have blunted or led to some level of dysregulation. I will go back to the dam analogy. There is definitely a plausible working hypothesis. We do not know that for sure, but it does make sense from the ability to drive additional current and voltage. To address your question directly, we do not see this. If this is a factor, we do not see this at all in the dual combination. Those tracings and the behavior of the channel based on this model look very much like wild type in terms of behavior and patterns with the dual combination. Yeah, Kambiz, I think that is really what Charlotte said. It is really critical. We want to drive as many patients to normal CFTR function as possible, because if we do that, we believe that is ultimately what is going to drive the best efficacy for patients. What those tracings clearly show us is that our dual combination more closely replicates wild type than the add-on. To your question around 451109, that would be a similar story in terms of the tracings, if we had those listed here. That dual combination would also look like wild type at Emax concentrations. If you remember, we put those both into the phase I dual combination. We selected SION-451 and SION-2222 because of the profile. We exceeded the PK targets, the safety and tolerability profile is favorable at the go-forward doses. It was the more favorable of the two options based on the totality of the data, including the phase I dual combination. Thank you. Thank you. Our next question will come from the line of Gaurav Maini from LifeSci Capital. Your line is open. Hey, everyone. Appreciate the color and update here. Just one from me. Just given AscenSION's moving forward with SION-451 and SION-2222, being that that's a corrector, I guess is there any assumed ceiling on CFTR function given there's no potentiator in this regimen moving forward? I'll start. This is Charlotte. We don't believe there's a ceiling when CFTR behaves normally or with, again, to go back to those behaviors and what we believe is the regulation that looks like wild type. Our hypothesis is that when an NBD1, when SION-719 was added to Trikafta, specifically, the ability to drive further CFTR function in that system was limited or blunted. So again, based across the totality of the data, we don't see what looks otherwise like a ceiling potentially with the dual combination. We know that in the clinic, we know that upwards of 2/3 of patients who are on standard care don't yet have normal CFTR function as measured by sweat chloride. So that would correlate to us with the ability to further drive additional CFTR function if there isn't this potential biologic blunting. Thank you. One moment for our next question. Next question will come from the line of Debanjana Chatterjee from JonesTrading. Your line is open. Hi, thank you so much for taking my question. This is Avni on for Debanjana. Again, congratulations on moving forward with the new trial. We just had a few quick questions. The first one is talking a little bit more about trial design. What would be the time to enrollment? I know you guys said that there aren't specifics that you guys are talking about, but could you tell us a little bit more about how long you think it'll take to enroll? Also whether you're looking at just U.S. patients or ex-U.S. patients. I will start with that. So when we do initiate the trial, we will have more specifics. Those kinds of questions are great questions, but those are the kinds of things that we'll be providing more information on as we initiate the trial. Yeah, and just on the trial design and the timing of enrollments, it really is important for us to initiate in Q1, so that's the guidance we're giving. It's much easier to know what that enrollment's looking like once you start to enroll the study. So at this date, what we're comfortable saying is initiation in Q1 2027. We're finalizing the protocols. We'll give more information as we continue to progress. But we're very excited about starting the study and closing the chapter on PreciSION CF and moving ahead and looking forward to delivering new options for patients. Awesome. Just a quick follow-up. Will you be doing any liver monitoring in this trial? There will be a whole robust, very typical stage appropriate set of safety monitoring and monitoring, and typical consistent with the small molecule sort of pattern in CFTR modulators. So we'll be looking at everything just as appropriate for this stage of study. Okay. Thank you so much. Thank you. That is all the time we have for today. Thank you for participating in today's conference call. This does conclude the program. You may now disconnect. Everyone have a great day.