Sionna Therapeutics Aktie

Good morning, everyone, and thank you for joining us. It's my pleasure to introduce the Sionna team. With us, we have Mike Cloonan, President and CEO; and Charlotte McKee, Chief Medical Officer. Mike, Sionna is sitting ahead of first proof-of-concept data from its NBD1 stabilizer approach in cystic fibrosis, which is expected this summer. In this context, how is the company positioned data-wise over the next 12 months?

Yes. Well, first, Salveen, thanks for having us. It's great to be here with you. Thank you, Goldman, for hosting us as well. And yes, so as we think about -- you've hit it on the head. We're really focused right now on that summer of '26, as you articulated, we have 2 different data readouts happening in the summer of '26.

We have our Phase IIa proof-of-concept study, which is the PreciSION CF study, where we are testing our 719, NBD1 stabilizer on top of Trikafta in a sweat chloride-based study that really is meant to demonstrate that NBD1 is mechanistically different from the components of Trikafta, but also synergistic with them that we can improve CFTR function as defined by sweat chloride in a clinically meaningful way. So our bar is a 10-millimole sweat chloride improvement, which we ultimately think will then translate into FEV1 improvement, which is obviously important in CF. This is not an FEV1 study per se, but the sweat chloride reduction that we deliver in this study will give us a lot of confidence that FEV1 will follow.

And then lastly, it gives us the opportunity to show and demonstrate the translation of our CFHBE assay, which, you know, is very important, and we're very fortunate to be able to leverage that in CF. So that's the first study that's happening this summer. And then to your point, that will then trigger what comes next, and I'll talk about the strategic decisions that we have to make. But we also have our dual combination data set that is also coming in the summer of '26, which we are testing our second NBD1 stabilizer 451 in combination with 2 other drugs in a 2-drug combination.

So we have 451 in combination with Galicaftor, which is SION-2222, a TMD1 corrector. And we're also looking at 451 in combination with SION-109, an ICL4 corrector. We'll have that data in the summer of '26, and that data is healthy volunteer Phase I data, which will have PK/exposure of the 2 drug combinations as well as the safety and tolerability of those 2 drug combinations. And the goal of that data is to help us select which of the 2 drug combinations we would then advance into a CF patient study. So that -- we're hyper focused on the summer of '26 and getting that data and then that ultimately will dictate the path forward. And we may get into this, but I think one of the key -- the 2 strategic decisions that we have to make with those 2 different data sets are which dual combination we're moving forward.

And then the second is, do we continue to progress the add-on forward. So you've heard us talk about this in the past that we're waiting for that data to see the positive data from that study, but also to see can we raise the level of capital that we would need to pursue both paths, both the add-on path and the dual combination. We are encouraged if we see positive data that, that is a commercially viable approach to have the add-on move forward, but we also want to make sure the capital is available to us to do that.

So if we're at the time of data, we'll announce the data, but we would also announce what the strategic decisions are and then what you can expect in terms of next steps and the data that would come post that, right? After the summer of '26, it would lay out the next chapter for Sionna and then we get into some of those timelines going forward.

I want to jump into the program before that. If you were to take the add-on forward, how would you translate from the add-on data you get now versus the Alyftrek, right, as the bar and then also your doses, you're at a lower dose now and you're going to move forward with higher doses on the forward.

Yes -- so I'll start, and then I'll let Charlotte talk to me a little bit more about what that future design would be. So if you -- as you're referencing a couple of things in there. So if you look at our target that we've set for the add-on, which again, is on top of Trikafta, we have set that bar as 10 millimole sweat chloride improvement, and that's in homozygous F508del adult patient population. That's the first study that we're doing.

And when you look at -- again, that's the clinically meaningful bar that has been set by the community. If you ask the community what is clinically meaningful improvement beyond the standard of care, that's what you consistently hear back is 10 millimoles of sweat chloride is clinically meaningful, would get the community excited if you deliver that level of efficacy. And that's also because not only is sweat chloride in and of itself important, right, to improve outcomes for patients.

But if you hit that level of sweat chloride, the expectation would be that we would deliver an FEV1 improvement in our later studies of something on the order of a 3% improvement, a 3 percentage-point improvement in FEV1. So that's where it starts from. And then if you look at apples-to-apples, Alyftrek in adult homozygous patient population, they delivered about a 3-millimole sweat chloride, and they were noninferior on FEV1 in their Phase III studies. So we not only would we be above the Trikafta by that level, but a significant improvement beyond where Alyftrek has gotten to.

So that's really important context, right, when you think about what this data is going to show and then relative to Trikafta, but also the apples-to-apples comparison with Alyftrek. And then if we make the strategic decision to your question, Salveen, of moving the add-on forward, we would absolutely incorporate the ability to add 719 to either Trikafta or Alyftrek moving forward. And I'll let Charlotte just talk a little about what that next step could be.

Yes. So the next step, again, if we were to move this forward, would be dose ranging. And we would -- as Mike said, we'd be looking at the appropriate dose range. We have said -- you've heard us say this add-on scenario in general, both only needs a low dose or concentration of an NBD1 stabilizer because of the power of that mechanism. And when we think broadly about the potential of embarking on an add-on program to standard of care, there are many reasons why keeping that dose low has other advantages from safety and tolerability, potential DDI.

So we would envision even if we were going to take this forward, we'd envision remaining in a low dose because that's all it looks like we need. Now it would be driven by the data from the proof of concept and whatever dose range we were looking at in the next dose-ranging study, we would obviously be data-driven and have what we would consider an appropriate dose range to prepare us for Phase III for Phase III dose ranging. And we would be looking -- if we were to go into that next step, we'd be looking at probably at least exploring both Trikafta and Alyftrek because mechanistically, it's the same mechanisms.

Ahead of the top line Phase IIa data that we're going to see for 719 as an add-on to Trikafta, can you contextualize this 10 millimolar per liter bar that you've set with the anticipated functional improvement this would provide and speak to your confidence in actually achieving this?

Yes. So I'll start with sort of why we said it and what's the context and the relativity of it, then Charlotte can actually speak to what does a 10-millimole improvement mean to the patient? I think that's also important. But if you look at the context behind the 10-millimole, as I stated before, we've asked the question for years of the community for a new option for patients, right, what would be meaningfully different from the standard of care, both Trikafta and Alyftrek and consistently what comes back is if we can deliver a 10-millimole sweat chloride improvement above Trikafta, that is a clinically meaningful bar that you've achieved.

And that's very meaningful to the community, to people living with CF and their families. And I'll let Charlotte talk about what that then could mean in terms of quality of life, life expectancy, et cetera. But it really comes from the community has defined this very clearly, and it's been consistently defined the same way. We do take into context, even this is an add-on to Trikafta, as we've talked about in the future plans, what we would do.

We do look at this also in the context of Alyftrek, right, in that we see that in the same patient population, this homozygous adult patient population, F508del, they delivered around a 3-millimole sweat chloride non-inferior on FEV1. So we look at that as now you have the options for Trikafta and Alyftrek. And our goal is always to be how do we drive to superiority? How do we set the bar high enough that we're hitting that clinically meaningful bar that would give us an efficacy advantage over the standard of care, and that 10 millimoles is really important.

And then I'd say the third thing that is critical is that when you look at -- this is a sweat chloride-based study, as you know, the Phase IIa PreciSION study is sweat chloride based with a target of 10 millimoles. It's not an FEV1 study. But the approved clinical endpoint, we know, in CF is FEV1. And so our goal is if we've continued the program is to show FEV1 improvement as well as we go into later-stage studies. If we can deliver that clinically meaningful bar on sweat chloride of 10, the confidence that we will achieve that 3 percentage-point improvement in FEV1 should increase because when you hit that 10-millimole sweat chloride bar historically in CF, you've now got outside the noise range.

As you know, there's a strong correlation between sweat chloride reduction and FEV1 improvement. That correlation becomes stronger the more sweat chloride reduction that you see. And that 10-millimole bar has traditionally been where that correlation becomes stronger. Double digits or more is where you start to see that correlation strengthen.

So that's the other reason why for us, hitting the clinical meaningful bar is important. Also the confidence in the ability to then see FEV1 in the later-stage studies increases and then the relative bar of both Trikafta and Alyftrek. So that's how we set it, why we're confident if we deliver it, it's very meaningful. But I'll also let Charlotte talk about how does that then translate to patients.

Yes. So actually, we have a -- there's a huge vast data set over years showing us that lower sweat chloride, better CFTR function is better. And we know that if we just look across the approved modulators, the lower the sweat chloride, the better the CFTR function, the better the short-term endpoints are, and that speaks to things like FEV1, for example, but also the better the longer-term endpoints are.

And sometimes some of those take large registry studies and many years to show, but it's been very, very clear that through line, the better the sweat chloride, the better the CFTR function, the better the complications are, the better the pulmonary exacerbation rates are. And then ultimately, those have translated quite consistently into improved lifespan as well. So it's been a really nice through line. To us, it just points this massive arrow towards what's possible if you really can improve CFTR function.

And interestingly, it is consistent when you think about how Vertex has messaged, right? Every reduction in sweat chloride matters, right? Lower sweat chloride is better. And even as like Alyftrek, sort of a modest 3-millimole improvement has been demonstrated that they're seeing switching. They're seeing patients come off even for that level in the homozygous population. So for us, again, hitting that 10, we know that's meaningful, and it's going to drive some of those same benefits that Charlotte talked about.

I guess in that context, right, is the 10 bar really a 13 bar when you take Alyftrek into consideration?

Yes. No, this is an add-on to Trikafta, right? So the 10 bar is the right bar to have in this. As we move forward, as we start to think about if we advance the add-on and then we take the Alyftrek arm, our expectation would be we should see a similar level of benefit on top of Trikafta.

So whatever that baseline is, we would expect to see that 10 millimole or more. Because as you know, the mechanism of Alyftrek is the same. It's correcting the protein the same way that Trikafta does. They've swapped out some of the compounds, right, in the triple drug combination, but the mechanism of action is the same. And so NBD1's effect and impact to both Alyftrek and Trikafta, we would expect to be similar because the mechanism is the same.

We looked at prior CF trials and historically, a 10-millimolar improvement in sweat chloride can be a little noisy sometimes with the translation with regard to the majority of patients impacted. How confident are you in the translatability in this patient population?

We're very confident. I would say just for all the reasons that Mike alluded to before, really that 10 all roads lead to a 10. And one of the nice things about predicting a correlation to FEV1 improvement with that 10-millimole per liter bar is that that is where you start to be outside of the noise. We hope to be the ones actually probing the specific dynamics of the sweat chloride FEV1 correlation as you get into higher ranges of CFTR function.

And you look across different mutation groups, those dynamics may be slightly different, mutation group to mutation group. But what has been very clear is that if sweat chloride is improved or CFTR function is improved substantially and to us, that's into the single digits, then FEV1 has improved. And we're very, very confident that we will be able to demonstrate that with the sizes of studies and the programs that we're thinking about in the future.

Great. At a high level, can you describe the patient's baseline characteristics here and how these will inform the study's outcome? And one of the things is one can lower sweat chloride -- or sorry, improve upon sweat chloride, right, in FEV1. But there's a level of 30 or so, right, where you're getting patients into this functional curative situation. So how do you think about that in the context of your data?

Yes. So what we're trying to do -- so this particular study, while we're very excited about the study, and it's going to answer some really important questions. It's not going to answer every single question. For us, what we've done with this study, the way we've designed it is to probe the biology and really to take -- our goal has been to enroll a population of patients that are stable on Trikafta and that had what would be a typical, kind of, expected response to Trikafta with respect to CFTR function and sweat chloride.

And so that -- so we are trying to run this right down the middle in terms of enrolling these patients. And we haven't described exactly the eligibility criteria, but you can imagine conceptually, we -- if you just look at the range of [Technical Difficulty] data points in patients who are stable on Trikafta. We're not looking to enroll patients who are already in the normal range, for example, because not to say that they wouldn't improve, but that's going to be a smaller dynamic range.

And also, we're not looking to enroll patients who, for whatever reason, kind of didn't have an expected response to Trikafta, they also may respond to an NBD1 stabilizer, but this is not the study for us to probe that. So really, we're looking for patients right in the middle, but to maintain some dynamic range to prove that hypothesis and the biology that once those patients -- and this is -- we are enrolling those patients who have gotten all the benefits they possibly can from Trikafta already, stable on that, what else does NBD1 stabilization do above and beyond that?

So remember, a small, efficient study to answer those questions. As we think about larger studies moving forward, we absolutely can start to open up that criteria. And as Charlotte said, there's no reason to believe NBD1 couldn't help patients that are already in the normal, maybe even get lower sweat chloride or these patients that are an outlier on the high end of sweat chloride couldn't benefit.

This is just isn't the study with the few number of patients that we have. We really want to make sure we're answering the right questions that will allow us and enable us to sort of expand going forward into future studies.

Do you think in the trial, so it's 16 patients, do you think that the data will be pretty consistent across the patient group? And do you plan to share patient data on an individual per patient basis?

Yes. So exactly how we'll have top line data sometime this summer and exactly what level we share first versus in a medical meeting is to be determined. We have -- because we know a lot about the characteristics of sweat chloride in this population and even in patients who are on the standard of care, we've built the potential for some variability into the powering and the study design.

So this will be -- we're expecting like you would -- like you've seen with every single modulator trial, there's going to be a range, right? But the -- what we're looking for is the mean change and an expected variability.

Yes. It's probably too small for like a true responder analysis, right, with a few patients, but there could be some added color and context that we can provide around the endpoint is mean change in sweat chloride, but there may be some additional color we can provide, like Charlotte said, either with the top line data or at a future study. But it's for a true responder analysis, it's too small to really to see that, but there's some extra color and context we can provide.

And while the Phase IIa is powered for sweat chloride, how are you planning to bridge the biomarker data to FEV1 improvements in your upcoming pivotal designs to, kind of, ensure a clear path to regulatory approval, not that you need FEV1 now for regulatory approval.

No, we would. Yes. Well, for superiority, right? -- non-inferiority, you can have a superiority, but we fundamentally believe that FEV1 is still going to be the registration endpoint. And so Charlotte can talk about as you go to later-stage studies, the powering, right, is what ultimately matters.

Right. So the next -- if -- let's just take as a potential add-on to standard of care, if we were taking that path forward, the next step would be dose ranging. And so that means more patients, a dose range, a response, a dose response sort of paradigm.

And we would be looking both at sweat chloride and at FEV1 in the -- with the goal to identify clearly the kind of dynamics that our drugs have with respect to both sweat chloride and FEV1 that would allow us to then power a Phase III study appropriately. So I have full confidence that really with the next -- especially the next set of data from a dose-ranging study that we know exactly what we would go into a Phase III study powered for.

Explain for us, given one of the study's goal is to validate your preclinical assay here, how you would think about that in the context of this data read?

Yes. So if you think about, again, that 10-millimole bar that we talked about before, if we achieve that, not only would we have hit the clinically meaningful bar for the community, it would also validate our assay because that's what we've gone in saying. This is what we believe we can do based on our assay predictions. Now we'll have a wealth of data to pull it to even though it's a small data set, it's a two-way crossover.

So we'll have a lot of information to glean from this study. But at the end of the day, if we hit that bar, we have validated the assay. And there may be some things we learned that we can even refine slightly the assay, right, just data points that may help us even make it a tighter prediction. But at the end of the day, we will have validated if we hit that number. And why that's important, not only for the add-on, but also for the dual combination because as a reminder, the dual combination is the Phase I healthy volunteer data set. We're not going to yet have CF patient data.

But the dual combination that we select to go forward, in part, is going to be based on our assay because we -- the thing we're going to base our selection of the 2-drug combinations on is going to be is do we see any safety or tolerability separation in our 2-drug combinations and what's the efficacy potential of those 2 drug combinations relative to each other and the standard of care that we derive from our assay.

So the proof-of-concept study, the PreciSION CF is going to give us that validation of the assay if we deliver that 10-millimole or more advantage. And it's going to then give us more confidence in the prediction of the 2-drug combination going forward because we have validated the assay. So even though they're separate studies, there are benefits to the proof of concept to our 2-drug strategy, the dual combination strategy that we will glean from the POC.

Do you think that you'll need to see data outside of the homozygous 508del (sic) [ F508del ] population to kind of fully validate the assay? Or you think just this population alone could do that?

Yes. So we -- so our -- as with most labs that run the CFHBE assay because of how you get those cells, the majority of our data in the CFHBE assay are in F508del homozygous cells because those are the most common genotype. And if you think about what you're testing with that, that's 2 versions of the F508del allele. So all of the CFTR in that system is mutated F508del CFTR.

And so if you then take those data consistent with what's been shown for the approved modulators, the next largest population by clear genotype is F508del on one allele and then null or minimal function on the other allele. There, you're just testing one version of exactly the same mutated CFTR. So those data are very completely applicable apples-to-apples to that. And then we know that it is up to 90% of people around the world have one copy of F508del and then either the second copy of F508del or something else on that other.

So we absolutely believe with good reason and data that the F508del homozygous CFHBE data are 100% applicable to other F508del mutation, heterozygous mutation groups. But also, we do some -- a smaller amount of work in our CFHBE assay with, for example, F/MF HBEs. So we know what the different correlations and dynamics are, and they are all very applicable and comparable to the homozygous population.

Moving to your Phase I dual combo study here. So what are the key pharmacological or safety differentiators that you're looking for from the Phase I healthy volunteer trial data this summer from the NBD1 stabilizer 451 in combination with Galicaftor, so 2222 and 109 to decide which proprietary dual combination you want to advance into Phase III.

Yes. So it's really -- we're testing 2 different 2-drug combinations, as you just articulated, Salveen. And the goal of that study is to generate enough data that is going to help us select which of those 2 drug combinations we're going to advance into CF patients. And it's going to be based on the safety and tolerability profile of the 2 different dual combinations. Do we see any separation as we've tested different doses, and does one have an advantage versus the other as it relates to safety and tolerability? That could be one of the ways we choose them.

And then the other is going to be where we really over-indexed in all of our strategy here is to the efficacy. And so what we plan to do is to select the best dual combination, assuming well tolerated and safe that hits the highest level of efficacy relative to the standard of care. So our target [Technical Difficulty] product profile for the dual combination has the same efficacy bar as the add-on. So we are seeking at least a 10-millimole sweat chloride improvement above the standard of care for our dual combination, and then that would translate into an FEV1 benefit.

So both the add-on and the dual combination have the same clinical bar to be superior to the standard of care by at least a 10-millimole sweat chloride and then that 3% improvement in FEV1. So we have the CFHBE assay to leverage. So as we get the PK and the exposure of the different doses we're testing of the 2 drug combinations, we can then put that back into the assay and determine where are we on the efficacy bar.

And if 1 of the 2-drug combination gets us higher, that is ultimately one of the ways we'll select the best dual combination to move forward. So again, it's both safety and tolerability, but it's also the PK exposure profile that we achieve that when mapped back into the CFHBE assay gives us the highest level of efficacy.

You brought up an interesting point before about when we think about the functionally cured population, I think it's about 1/3 -- do you -- so this idea that if you were able to even [Technical Difficulty] lower chloride further that -- so can you actually benefit those patients in that cured [Technical Difficulty].

Less than 30 millimoles.

So it's unknown. There haven't been enough of them studied over longer periods of time to know if a pharmacologically improved CFTR function below that bar of 30 provides a benefit. So what we do know is lower is better and 30 has been -- it's been a cutoff based on epidemiology and diagnosis, et cetera.

I think it remains an open question, but our goal, as Mike has said, is lower is better, and we're going to drive as low as possible. So we -- just to correlate that to how we're thinking about future studies, we wouldn't expect to have the same sort of rigid criteria that we have for this very first proof-of-concept study with respect to eligibility and CFTR function in later-stage studies.

And I would just say that -- so when you think about everything Charlotte said is true and that lower is better, but we also do think about where is the unmet need the most, right? And so those 1/3 that are below 30, that unmet need is lower than what you'd say those 2/3 that are not yet at normal.

So when you think about who can most benefit, we are sort of targeting that 2/3 that we think can really drive the most benefit and maybe we can move more of them to the normal range, right? That would be the goal. And then as Charlotte said, maybe there's an opportunity with -- as the broader patient population opens up in our label that anybody could benefit from it. But at the end of the day, where the target should be at least initially is where is the unmet need the most. And that clearly is for those who are above 30.

And going back to the dual combo program here, how do the complementary mechanisms of 109 and Galicaftor specifically [Technical Difficulty] protein in a way that [Technical Difficulty].

Yes. So if you go back to the biology, what nothing is directly being stabilized with in the current modulators is NBD1. So in our dual combinations, whether it's paired with Galicaftor or whether it's paired with our ICL4 modulator, SION-109, what really is left unaddressed by those 2 mechanisms is directly stabilizing NBD1.

So no matter which -- what the combination, the NBD1 stabilizer is really the most powerful component of the dual and addresses the thing that is not yet fully addressed with the approved modulators. What we also know is from both previous science, second site mutation data, et cetera, really, if you can stabilize NBD1 directly, just a single interface domain stabilizer or modulator, which Galicaftor or SION-109 each do is enough to potentially improve the function to wild-type.

But you can't wait for data to answer...

No, you couldn't have said it better. We are super excited about the summer that's coming. It's really an exciting time for us, for the community. And as we've said, answering a lot of questions, it will tee up what comes next, and we've got some really key strategic decisions to make.

But as you know, we're trying to do something very, very unique, right? We really are on a mission to transform the treatment paradigm in CF by leveraging the unique and differentiated NBD1 stabilizers in these combinations that have the potential to improve outcomes for patients and drive clinically meaningful benefit for them.

So we are in this really unique position to potentially positively disrupt this market and bring new options for patients. And that's really what our focus is. And the summer is such an exciting time for all of us, and we very much look forward to turning over those cards and being able to report out the data and then what the next steps for Sionna is.

Great. Well, with that, Mike and Charlotte, thank you so much.

Thanks Salveen.

Always a pleasure. Thank you.

Good morning, everybody. Thank you so much for joining us here on Day 2 of the JPMorgan Healthcare Conference. My name is Bhavana Balakrishnan. I am an associate with the Healthcare Investment Banking team. Thank you for joining us here for the presentation of Sionna Therapeutics. With us, we have Mike Cloonan, President and Chief Executive Officer; Elena Ridloff, Chief Financial Officer; and Charlotte McKee, Chief Medical Officer. Over to you, Mike.

Thank you so much. Great to see everybody. Thank you all for attending today. It's a pleasure to be with you, and thank you, JPMorgan, for the opportunity to present. These are our disclosures. We will make forward-looking statements today, actual results may differ from those statements. Sionna, as you may know, is on a mission to revolutionize the treatment paradigm in CF by leveraging our first-in-class NBD1 stabilizers in combinations that have the potential to drive clinically meaningful benefit above the standard of care. We have a rich history, even though we were only formed as a company in late 2019, we were a spinout from Sanofi at that time but the science behind our programs originated at Genzyme over 15 years ago, and that's an important part of the story because we wouldn't be where we are today going after this very challenging target in NBD1 without the level of perseverance and investment that was made between Genzyme and Sanofi.

We are really well positioned at this point to positively disrupt the CF market with the new mechanism of action in NBD1 and the combination strategy that we are pursuing. There really are 4 key parts of the Sionna story that we'll touch on, on the presentation, and I'll start here with a summary. The first is the unmet need. Despite the advancements that have been made in CF over the last several years, the unmet need continues to be high in CF. And you can define that through multiple ways. You can look at it from a quality of life perspective, a life expectancy or what we often talk about, getting patients to normal CFTR protein function. And we know today that for patients who are on the standard of care, only 1/3 of those patients get to normal CFTR function. So that leaves 2/3 having an opportunity to achieve higher levels of CFTR function.

We believe we have an opportunity to do that with our novel mechanism in NBD1 and if we can do that, if we can deliver meaningful new options for patients that potentially raise the efficacy bar, not only would that be an amazing opportunity for patients to have more options, it's a significant commercial opportunity. The CF market today is a $12 billion monopoly and it's growing to $15 billion-plus by the end of 2030. So the core of what you'll hear us talk a lot about is NBD1, this target. It is not a new target. It's not a new mechanism. It has been well understood and well studied in the past. The biology behind NBD1 is very clear in this space, but it has long been considered this undruggable target, the holy grail in CFTR correction. We are here today with multiple clinical assets on NBD1 and about to refute that undruggable label that has existed for many, many years. And NBD1 really is the key to fully correcting the protein as we'll talk about later in the presentation.

And we also know that none of the approved modulators directly stabilize NBD1. So it is truly novel, differentiated and first-in-class. We are also fortunate to leverage the gold standard in-vitro CFHBE assay, which has been demonstrated to be highly predictive of clinical outcomes. We have a lot of confidence in our CFHBE assay, and what it tells us is possible with our combinations. And when we look at our multiple runs of our CFHBE assay with NBD1 in combination, it shows us that we have the potential to raise the efficacy bar in CF through combination therapy. And then that speaks to the last part here, the fourth item. As much as NBD1 is a critical part and the differentiated part of our portfolio, we are also investing in complementary mechanisms that when you combine them with NBD1, this is where we have the potential to deliver wild-type levels of CFTR function, fully normal. Let's talk a little bit about the biology of NBD1. Why is it so important? And why is it so critical in what we're doing.

We know what causes CF. It's genetic mutations to the CFTR gene that impacts the CFTR protein. The #1 genetic mutation that causes CF is F508del. Approximately 90% of patients have a form of that mutation. And if you look at the graphic here, you can see F508del, that mutation resides within the NBD1 region of the protein. And what that mutation does is it causes NBD1 to irreversibly unfold at body temperature. So it is creating this instability not only in NBD1, but in the protein, crippling its folding, its ability to traffic to the cell surface and then the overall functionality. The standard of care, as you may know, TRIKAFTA is a triple combination and it is correcting different parts of the protein not directly stabilizing NBD1. It is correcting around NBD1 by correcting ICL4, TMD1 and TMD2. Therefore, it's partially correcting the protein and NBD1 is still unstable. So we see this as a very novel opportunity for us, as I said, to potentially disrupt the CF market.

And when we look at all of our preclinical data that we have on NBD1, when we stabilize and correct NBD1, it does something fundamentally different than the approved modulators to that protein. And one specific example of that is in our CFHBE assay, when we model the monotherapy, the single agent of NBD1, and we compare the level of correction to TRIKAFTA, a triple combination. That efficacy is nearly equivalent to the single agents nearly equivalent to the triple combination. So that speaks to the power of NBD1 and what it can do on its own. Our goal is to get as many patients to normal CFTR function. The way we do that is stabilize NBD1 and then correct just one other part of the protein to form a dual combination that has the potential to drive more patients to fully normal CFTR function.

Let's talk about the pipeline. We have a deep pipeline, both in terms of our NBD1 programs and the complementary mechanisms that I referred to before. Both our SION-719 and 451 NBD1 stabilizers have positive Phase I data, and they are both advancing to the next stage of development, but in 2 different ways. SION-719 at the top that you can see here, is advanced into a Phase IIa proof-of-concept study in CF patients called our PreciSION CF study. And we'll talk about that study and design in a little bit, but we're expecting to have the first patient data from an NBD1 compound 719 on top of the standard of care by mid '26, and we are on track to deliver that data. We also have 451 another NBD1 stabilizer that we are using as the anchor to our dual combination strategy that I described before. 451 is in a healthy volunteer dual combination study where we are combining 451 with one of our complementary mechanisms, 2222, which is a TMD1 corrector, and we are also combining 451 with SION-109, our ICL4 corrector.

That data, we also expect to have in the middle of 2026. This past year, 2025, we made meaningful progress across our portfolio and advancing the company. I spoke about the 2 NBD1 programs, SION-719 and 451 both completing their Phase I, having positive data, they both advanced to their next stage of development. 719 is now in the ongoing PreciSION CF study, our Phase IIa proof-of-concept study and 451 is the anchor to that dual combination healthy volunteer study that I mentioned before. We also completed our IPO earlier in the year, which has positioned us nicely from a capital perspective to have cash runway into 2028, well beyond those catalysts and milestones that I referred to in mid-'26. So let's talk about our 2 lead stabilizers for NBD1 and the Phase I data that we've presented in the past. If you look at the chart here, I'm going to first focus on the PK on the left and then the HBE curve on the right-hand side.

So this is 719, one of our first stabilizers that has completed the Phase I data. You can see on the left, the PK curves, we tested multiple doses of 719. The PK exposure is on the Y-axis, it's a log scale. And what I really want to point out, if you look at these 2 teal hash lines, one that says the add-on target and the higher one says the dual combination target. We leveraged our CFHBE assay to set very specific exposure targets ahead of the Phase I data. That assay helped us imply what the exposure is needed to deliver in order to hit clinically meaningful benefit above the standard of care. So as an example, that add-on target, the lower target represents a 10 millimole sweat chloride improvement over the standard of care, which we think will equate to a 3 percentage point improvement in FEV1 as well. That is the bar for clinically meaningful, and that's the target we set as one option to combine 719 as an add-on. The higher target is the dual combination strategy that I referenced before.

It's a higher concentration target because this is just 2 drugs coming together, NBD1 has to do more of the work in that scenario but the clinically meaningful target is the same, 10 millimoles of sweat chloride, 3 percentage point improvement in FEV1. The takeaway from the 719 PK study is that at every dose we tested, we exceeded that add-on target on top of the standard of care. And for every dose from 40 or above, we were above the dual combination target. We have selected 719 to advance as our add-on to the standard of care compound because of its potency, specifically at lower doses. Now when we look at the right-hand side, this is our CFHBE assay, that gold standard in-vitro assay I mentioned before. We have now plotted the PK exposure that we've achieved in that Phase I with 719 into our HBE assay. And a couple of things to point out. The assay measures chloride transport, and we have put the Y-axis into a relative scale so that you can compare us to the standard of care.

So if you look at the 1.0 reference point, that is TRIKAFTA, elexacaftor, tezacaftor, ivacaftor at the 1.0. You can see that same teal hash line that I mentioned before that denotes clinically meaningful benefit, 10 millimoles of sweat chloride when we add 719 on top of TRIKAFTA. And now if you look at that maroon shaded rectangle, this shows you the range of efficacy possibility that we have with 719 when we added to TRIKAFTA at our lower doses. And what this tells you is we have confidence we're above that minimum bar to deliver clinically meaningful benefit, all the way up potentially into wild-type levels of CFTR function, normal CFTR function. Now similarly, this is 451, our second NBD1 stabilizer. Similar plots, the PK on the left, the HBE on the right, what you'll see here is the same hash lines that I mentioned before, representing that clinically meaningful bar that we set ahead of the Phase I studies. And with 451 at every dose we tested, we exceeded that add-on bar.

And at every dose from 75 milligrams and above, we exceeded the dual combination bar. We selected 451 as the anchor to our dual combination because of how high the exposure we were able to achieve with 451. And in the dual combination, that's what's important, driving more exposure, the ability to drive higher levels of efficacy in a dual combination and it's an excellent opportunity for us to progress both 719 and 451, leveraging their unique differences. Similarly, on the CFHBE, it's the same relative scale comparing to the standard of care TRIKAFTA. You see that hash line representing the clinically meaningful bar and that same maroon shaded area. This is now the dual combination where we're combining 451 with just one other compound at the higher exposures. You can see here, we're above the bar for clinically meaningful benefit, all the way up potentially into wild-type levels of CFTR function. So very pleased to have that positive data for both 719 and 451.

Now let's look at the clinical strategy and our portfolio strategy and what comes next. So 719, as we mentioned, is going to advance as the add-on on top of TRIKAFTA. It has already initiated that Phase IIa proof-of-concept study, the PreciSION CF study that I mentioned before, and I'm pleased to say we are on track to deliver that data in mid-'26. We're very happy with the execution of the trial and the sites, and we look forward to sharing that data in mid-'26. And on the bottom, you see we have a parallel path for the dual combination where we're combining 451 with both 2222, one of our complementary mechanisms and also 109, one of our other complementary mechanisms. The goal of that study is to generate PK in combination of those 2 different dual combos and also assess the safety and tolerability profile of both combinations that we will ultimately select the best dual combination to progress from there to advance into a Phase IIa dose-ranging study in CF patients. We also expect to have that dual combination data, the healthy volunteer data in mid-'26.

So an important time for us to have both data sets. Strategically, just so everybody understands what we're doing here, our first priority in terms of advancements is the dual combination path. We think, ultimately, that has the best profile both for patients something that you could drive to higher levels of efficacy with just 2 compounds, potentially even a different tolerability profile. We think it has a real benefit to patients. The add-on to the standard of care, at this point, what we have said is if that data is positive, we will have an opportunity to assess whether we would progress both paths forward. Will we continue to progress the add-on and the dual combination. We know both of these paths are commercially viable and can be co-positioned that they can work together in the marketplace with multiple options for patients. But what we want to make sure is that we have the capital to progress both of those pathways.

So when we have the data, we'll assess that data, and we'll make that decision on the add-on whether to progress that as well as the dual combination. Now just a quick background on the PreciSION CF. This is an elegant, efficient study design for the proof of concept of 719 on top of TRIKAFTA. As you can see, this is a 2-way crossover study where each patient will act as its own control, and we need less than 20 patients to power this study to a sweat chloride improvement of at least 10 millimoles. So you'll continue to hear that number from us, 10 millimoles of sweat chloride is the minimum threshold that we have set for clinically meaningful, which we also expect in later stage studies to demonstrate FEV1 improvement. This study is a sweat chloride test, our sweat chloride study is not meant to show FEV1, but we fully expect if we deliver that level of sweat chloride improvement, we will see FEV1 in later-stage studies. So when we fast forward to mid-'26 and what does success look like for Sionna specifically on the CF -- PreciSION CF study.

The first is that 10 millimole sweat chloride bar. If we achieve that, we know we have hit the clinically meaningful bar that would make a meaningful impact for patients in CF. And so that's the first definition of success. We know that, that bar is the right bar to achieve for 2 reasons the historical benchmarks in CF have demonstrated a 10 millimole sweat chloride improvement that also has the potential to equate to 3 percentage points or more of FEV1 is clinically meaningful. We've also engaged with the community to understand from them, has anything changed? What would be clinically meaningful in your mind to get excited about a new option in CF, and it is very, very consistent. And it's also important to note that Alyftrek, the new triple from Vertex, in the same homozygous patient population where we are projecting a 10 millimole sweat chloride improvement, Alyftrek delivered 3 millimoles of sweat chloride improvement.

So that's the relative comparator to think about. If this study is successful, and we've delivered that 10 millimoles, as we said, we will make the strategic decision as to whether to continue to advance that program forward. But what it will do for us is it will demonstrate in this study that NBD1 is mechanistically different from and yet synergistic with the components of TRIKAFTA. The first time we'll be able to demonstrate NBD1 in CF patients. It's also the first chance that we have to validate our CFHBE assay in CF patients, a very important milestone that will help us build additional confidence in our CFHBE model which will then translate to the dual combination strategy as well. So a very important study on the horizon for mid-'26. Let me just quickly touch base. I mentioned the unmet need and this commercial opportunity. It's worth showing this graphic, which is a post-marketing CHEC-SC study that is showing sweat chloride levels for patients on approved modulators.

If you look to the far right, this is patients who are on TRIKAFTA, the black dots all represent an individual patient and their sweat chloride level. What is important to see here is, yes, you see significant improvement when patients go on TRIKAFTA, which is a great benefit to the patients. But what you also see is you see where the normal line starts, where normal sweat chloride is, which is 30 millimoles or less only 1/3 of patients on TRIKAFTA achieve that normal level of CFTR function. You can see all the patients above normal. This is important to us as we think about trial design, patients that will enroll. We want to deliver more of those 2/3 of patients that are not fully normal to get to that level of sweat chloride. And then when we think about the commercial opportunity, this is a large rare disease that's well established. Over 100,000 patients worldwide. Our target population, as we've talked about, is the 90% of patients who have the F508del mutation. You've seen the unmet need that exists for patients not getting to normal.

We know that more options for patients are needed. And if we can deliver that in this $12 billion market that is growing, we could potentially add meaningful benefits to patients and drive significant commercial uptake for Sionna. So in closing, Sionna is well positioned to positively disrupt the CF space. We have first-in-class NBD1 stabilizers that in combination show the potential to deliver clinically meaningful benefit above the standard of care. We are well positioned. We have an excellent team. We have novel and distinct science, and we have the capital to pursue our strategy, and we have near-term catalysts on the horizon. So we're very much excited for the coming year and the continued execution to set up these milestones going forward. So with that, I'll stop, and we'll open it up for Q&A.

Okay. Here's a bit of a personal question. But have you ever considered going after HETHS with 508, though?

Yes, we will. I'll let Charlotte describe the plan. The initial study is just homozygous.

Right.

The broader plan will include HETHS, but I'll let Charlotte talk about that.

I think targeting a PD-1 stabilization in HETHS, and I happen to be one and my several -- my family members are, makes a lot of sense because it's actually not a silent phenotype.

Yes. Go ahead, Charlotte.

Yes. So our target population is basically anyone with at least one F508del, and that is certainly the majority of those patients are homozygous as a group, but absolutely, that is part of our long-term strategy.

I have a question. As you think about your dual prioritization strategy and how would you compare the commercial opportunity for the 719 add-on versus the 451 dual combo?

Yes. Elena, you want to take that?

Sure. So as Mike was articulating, we think there's attractive commercial opportunities for both of these profiles. So today, this is a $12 billion market expected to grow. If we can deliver what we expect as far as improving efficacy, both either with an add-on or with a dual, there's a tremendous population, 2/3 of patients who are not today at normal. And as we've done a preliminary market research, what we hear is that there is a ton of enthusiasm for a novel dual combination. Today, TRIKAFTA and Alyftrek are 3 drugs, adding 719 would be 4. So to have 2 drugs that could potentially have a superior efficacy profile and potentially a differentiated safety profile, there's a lot of enthusiasm for that. As well, there's enthusiasm for patients who today are well -- there are patients who are happy with their current standard of care, but would like more efficacy. So we do think there's an opportunity where these could be either individually very successful commercial launches and also potentially co-positioned if we were to decide to pursue both and have a very nice commercial opportunity for either or both in the market.

And as you think about prioritization within the novel combo itself, like how would you think about your ICL4 versus your TMD1? And what sort of data do you need to see to be able to come to that decision?

Yes. Go ahead, Charlotte?

Yes. I'd say mechanistically, when we look at our CFHBE assay, either of those TMD1 or ICL4 modulators, they're both interface domain modulators. So either of those actually has the potential to fully correct CFTR function when combined with an NDB1 stabilizer. So mechanistically, we're really agnostic. So it really will be the PK and safety profile that really we see as we call this Phase I healthy volunteer study, our sandbox. So it will be really the components and their individual properties in combination with NBD1 stabilization.

And when you think about the data that both physicians as well as community need to see, what do you think is required and what is the bar to incentivize and sort of give comfort for the community to switch from SOC?

Yes, I'll start and then Charlotte can -- she has a lot of history in CF. And when we think about what we think the regulatory bar will continue to be in CF is FEV1, right? We think that's the primary endpoint, that in our later-stage studies as we move into dose ranging in the Phase II that will continue to be the bar. Sweat chloride is a very important secondary marker and the road to FEV1 improvement tends to lead through sweat chloride and which is why we're starting there. But we continue to believe if we want to show clinically meaningful benefit beyond the standard of care, it will be -- FEV1 will be the determinant of that, and we think that will drive the switching, the adoption because it is the marker that people look at specifically around efficacy in CF. I don't know, anything you'd add, Charlotte?

No, I would just reinforce, we do expect in our driving is just to reinforce to an improvement in FEV1. We see that possibility. And -- but then it's the benefit risk profile and on an individual patient basis.

And what can you learn from recent launches in this space, both in terms of bar for success as well as, as you think about launch in a few years? What are main learnings for you?

Yes. I mean I'd say that the most recent launch is Alyftrek, right? And I think it's still early days for Alyftrek to see what it will do. But when we look at the profile of Alyftrek relative to TRIKAFTA, which is the standard of care, what we see from the Phase III data is that Alyftrek was non-inferior on FEV1. So there was no improvement in FEV1 from Alyftrek versus TRIKAFTA. They saw a slight increase in sweat chloride in the homozygous patient population. It was 3 millimole improvement in sweat chloride, in the heterozygous patients, it was an 8 millimole improvement. So for us, we're setting the bar higher than that, right? We want to hit that 10 millimoles or more because we believe if you look at the history of the modulators that have been approved, when you're in that single-digit improvement in sweat chloride, sometimes you achieve FEV1 improvement, but just as often you do not.

And so we want to be outside the noise as it relates to sweat chloride and deliver that 10 millimoles or more, which we then -- fundamentally will help drive that FEV1. So what I think we're seeing is that without the FEV1 improvement in Alyftrek, with the sort of modest improvements in sweat chloride, we haven't seen the full uptake yet. But historically, I would say it's an efficacy-driven market, right? And when you have the FEV1 and the sweat chloride together, is where you have the potential to drive the highest level of adoption and the most benefit for patients.

You spoke in the beginning about the challenge of NBD1 stabilization. Can you just talk about kind of the journey where you are today?

Yes, happy to. It's a great question. It has been a journey, right? As I mentioned, the history there, it's taken us 15 years between Genzyme, Sanofi and now Sionna to have programs in the clinic. And so when you -- what really the challenge has been about NBD1, it's the binding pockets around NBD1 are very, very shallow. So it's a very challenging medicinal chemistry exercise to develop compounds that combine to NBD1. And over the period of time that this was being developed within Genzyme and then Sanofi, there were several learnings that took place to really help them break through and then Sionna took it to the next level. And a lot of that was a structure-based biology approach to developing these compounds where we really built the compounds up atom by atom, looking at the activity, leveraging the CFHBE assay.

We have over 150 X-ray crystal co-structures. It was a tremendous amount of effort that went into defining or thinking through these compounds and which ones could rise to the top and ultimately looking at activity in the assay to help us prioritize which compounds we move forward. There is history and that we know there have been other companies that have tried to tackle NBD1, Pfizer is one company that wrote an article about this back in the 2015, 2016 time frame after they took a long, hard run at NBD1. And even though they couldn't say it definitively from their work, their conclusion was this could be an undruggable target, and they specifically referenced the shallow binding pockets. So Pfizer tried.

We also know that Vertex has stated publicly, they have tried to crack NBD1. And I think the words they used was they couldn't optimize this target and to their credit, they found other ways to correct -- partially correct the protein. So it is a challenging target for sure. We're well positioned based on the history and the knowledge that we have, our IP estate protects us significantly. We continue to innovate and develop new NBD1 compounds even behind what you're seeing with 719 and 451. And so we want to continue to be a leader as it relates to NBD1 in the future.

How should we think about your runway and which milestones are you fully funded to?

Yes. So we ended Q3 with $325 million in cash and we have cash runway into 2028. So that takes us meaningfully past these milestones mid this year.

Any other questions from the audience? Mike, I'd like to turn it over to you in case you had any closing remarks.

I would just say, one, thank you for everybody for attending today, live and in person. It's a pleasure to have the opportunity to present. As we talked about, it's a very meaningful year for Sionna. We have set ourselves up for 2026 to be very impactful with our 2 programs that we expect to have data in mid-2026. The PreciSION CF study is enrolling nicely. We're excited to share that data when it comes in mid-'26, it will be the first time we'll be able to share NBD1 data in CF patients. And as I said, it's going to give us multiple opportunities to show the potential to increase CFTR function and to show our assay translation and CF patients. At the same time, we've got this opportunity with our dual combination strategy to select that best tool combination from that healthy volunteer study in mid-'26. Our team is outstanding, they execute really well. We have differentiated science. And as we've said, the capital is there for us to pursue it. So we very much look forward to future updates from Sionna's progress and future success. But a reminder, our goal is to transform the treatment paradigm in CF. Thank you.

Thank you.

Welcome to the third day of the Citi Global Healthcare Conference. So my name is Geoff Meacham, the senior biopharma analyst here, and we have Sionna with us on stage. So we have Mike, CEO; Elena, CFO.

And Charlotte McKee.

Yes. So welcome. I mean maybe just to kick it off, Mike, just give us like the 2-minute type of elevator pitch. I mean I know the category, you guys do, too, but I think for those on the webcast, maybe for a bit of a background.

Yes, happy to, Geoff. And first, thanks for having us. Great to see you, and thanks for Citi for inviting us today.

So Sionna, we are focused on cystic fibrosis, and we are attacking cystic fibrosis in a different way. We're going after a differentiated target called NBD1. It's not a new target that's been well studied, but it has long been considered this undruggable target. So we have this very differentiated approach. And our vision really is to transform the standard of care in CF with NBD1 being the anchor to that strategy.

As I'm sure we'll get into -- we have recently entered our Phase IIa proof-of-concept study with one of our NBD1 stabilizers, SION-719, that we're going to add that on top of TRIKAFTA, the standard of care in a proof-of-concept study to show that NBD1 is mechanistically different from the components of TRIKAFTA and that we can also improve CFTR function as measured by sweat chloride, a very important first step for us in the clinic. First time NBD1 is going to be tested in CF patients, and we expect that data in mid-'26. So that's one path with the add-on approach with 719.

And then our second NB1 stabilizer, SION-451 is the anchor to our dual combination strategy, where we're combining 451 with two other complementary mechanisms to test the safety tolerability and the PK profiles of our dual combinations with the ultimate goal of selecting the best dual combo that we would progress forward.

That dual combination strategy is our prioritized approach. We think that's ultimately the best profile for patients. We have the potential to add meaningful clinical benefit above the standard of care with just two compounds. And as many folks know, the standard of care today is a triple combination, three different correctors coming together. So we have an opportunity to do something very, very different with our dual combination approach, and we also have that data in mid '26. So very important time ahead of us, right? The strategy is playing out, and we have some data coming mid next year.

But we're really well positioned the IPO we did in February of this year. We raised $219 million, brought in some great new investors and that has really set us up to have capital into 2028. So beyond those catalysts that we have next year and gives us a lot of financial flexibility to execute the strategy. We've got a great team, we've got a Elena and Charlotte here with me today. But a great team back in Boston as well. So super excited to hear more about the story.

Yes. Let's take a step back before we start talking about the pipeline and the mechanism and obviously, the CF population, the sort of technology platform, the kind of the R&D platform. Talk a little bit about how you think Sionna is doing something unique and NBD1 focus is unique, but the kind of the discovery engine that you could backfill a number of assets in the pipeline with?

Yes. So if you think about our strategy, and NBD1 is really is starting there, we can get into further with the rest of the portfolio and how the research strategy, but maybe even go step back to history here, which is important, right? Because if you think about NBD1 not being a new target, and it has been considered this undruggable, holy grail target of CFTR correction, well known and have been studied by other companies, but it was given this label because it was very challenging to drug. Very, very shallow binding pockets exist around NBD1, and that's why it got the label as undruggable.

We are where we are today at Sionna in the clinic with multiple compounds, others even earlier in the portfolio and in the research engine because of the history. The legacy of Sionna, we spun out of Sanofi back in 2019 but the science behind our programs goes all the way back to Genzyme. Over 15 years ago is when these programs originated and the science behind them. We wouldn't be where we are today without that legacy of Genzyme that carried forward into Sanofi and then when we spun out, we were a dedicated CF-only company that could then advance these compounds in a way that was different than within big pharma. When you're competing for resources and trying to prioritize these compounds versus others.

But it's that -- leveraging that history, the level of investment, the perseverance that it took prior to Sionna spinning out is really important because we often get asked, "How did Sionna crack the code on NBD1, when you've got other companies that haven't been able to do that?", again, we wouldn't be where we are today without that effort that took place prior to Sionna, and we think it's one of those opportunities that shows the benefit of starting in big pharma rolling out into small biotech as a dedicated small CF-only company that has put us in that position.

And then when we think about the research engine, you're kind of referencing we've got NBD1 as sort of our core differentiator, but we're also in our portfolio of complementary mechanisms some that we in-licensed from AbbVie, some that we've developed internally that gives us an opportunity. We really have a franchise of CF options that when you can put them in various combinations with the ultimate goal for us is to raise the efficacy bar. We want to raise the efficacy bar through the combinations that we put together to create new, compelling options for patients, and we think there's room in this $12 billion market today in CF that's growing to $15 billion. We think creating more and different options for patients would be really beneficial and obviously, a very significant commercial opportunity.

One of the first approach is adding on to standard of care. So talk a little bit about what you guys view as the unmet need or the opportunity to further expand standard and then we'll talk about you and your individual assets.

Yes, I'll let Charlotte talk about the unmet need and how we want to approach that.

Yes. As important and impactful as the current modulators have been, we know from real-world data that as many as 2/3 or more of patients on the standard of care don't yet have normal CFTR function as measured by sweat chloride. And really more and more we strongly believe and we hear from the community, too, that, that really should be the goal. And so we do believe -- and if you look across the history of the modulators as they've been developed in waves, the lower or the better the CFTR function can be, the more that has flowed through to both short-term and long-term clinical benefits. So that's really what we're driving for. And we do believe that NBD1 stabilization is really the key to moving more patients to normal CFTR function.

That makes sense. Have you guys done market research in terms of the patients that are on a modular today, the ones that are suboptimal responders or the dropout of therapy, the reasons why and maybe that could help guide kind of how your product portfolio going forward?

Yes. I'll talk real quick and then I'll turn it to Elena to get into that specific question, Geoff. But I'd say if you go up a level, and what is our target population, right? Yes, there are patients today that maybe drop off the standard of care or have other challenges that we could definitely support going forward. Our goal really is to go after the same patient population as the standard of care. We expect our label would look very similar that this would be for all patients that have F508del mutation, which is 85% to 90% of patients have a form of that. And so we want to have as broad an opportunity to impact those patients. For the reason Charlotte said, 2/3 of those patients on the standard of care are not at normal CFTR function. That's ultimately the goal we should be striving for.

And I think interestingly, Vertex says the same thing. We are fully aligned with Vertex on that messaging point, which is we should be striving to get as many patients to normal CFTR function as possible. But Elena, do you want to get a little bit into the details?

Yes. So when we do market research, we're really testing that target profile that we think we can deliver, which is a dual therapy, that's our proprietary dual that could deliver above and beyond the standard of care from an efficacy perspective and be potentially differentiated from a tolerability perspective as well because it's two drugs instead of three. And when we test that profile, there is a lot of enthusiasm for something new in this broad population. We don't hear that would be specific to nonresponders. There's just general enthusiasm that, that would be a very compelling product profile for patients and physicians.

No, it's just interesting that you have all the Phase III data for, say, TRIKAFTA and for ALYFTREK, but in the real world, may have a different experience. And you just don't hear about that, right, from a lot of pulmonologists that maybe for various reasons like patients can't tolerate the highest dose, so they don't get the FEV1 that was promised. So Charlotte, you mentioned sweat chloride, so is that becoming more of a metric like in the community to help sort of put a patients kind of where they are from a maintenance perspective?

So I think it's still more of a research tool. And definitely, the experience with the modulators has highlighted the importance of sweat chloride as a really important clinical biomarker. Of course, all through the approved modulators which I had the privilege of being a big part of all through the approved modulators, sweat chloride was a really important secondary and supportive endpoint. So that will -- we see that as continuing.

I think we see still the opportunity to actually potentially improve FEV1 as well. And then in the long term, some of those other longer-term outcomes like pulmonary exacerbations, et cetera. And so we do believe that FEV1 lung function will still remain the registration endpoint and sort of the primary endpoint, and that's really what we're striving to improve by improving CFTR function substantially versus the standard of care.

That makes sense. And Mike, you talked about the strategy here with the add-on and then the ability to move up on the efficacy and improve the profile. So talk a little bit about the selection process between 719 and 451? What attributes of the compounds kind of drove your decisions of one path versus another?

Yes, we were really pleased when we ran the Phase I studies for both 719 and 451. We were expecting that maybe one would rise to the top, and we would just pick that one NB1 stabilizer, and we would advance it into our clinical development strategy, which was always contemplating as the first proof of concept to add on top of the standard of care while we were also in parallel going to be developing that dual combination approach.

When we got the data, what was -- we were really pleased with is from a tolerability safety perspective, there really was no separation between 719 and 451 in a positive way. They are both generally safe and well tolerated, and we are fortunate that, that wasn't a differentiator for either one of them.

And then when we look at the PK. So when we went into the Phase I, we have set two distinct targets, leveraging our CFHBE assay. We had set very distinct exposure targets that we needed to achieve in the Phase I for both compounds. We had set one target which was based on the add-on approach. If we add NBD1 to the standard of care, there is a lower target for that because NBD1 now is the fourth compound being added to this combination. And these -- they all synergize and work well together. So we had a lower target of exposure for an add-on. And then when we had a higher target for our own proprietary dual combination, which, again, is just the two drugs with NBD1 being the anchor. And in the 2-drug combination, we need more exposure of NBD1 because it has to do more of the work in a dual combination than it does in the quad.

So the -- when we looked at the data for 719 and 451, both compounds exceeded the add-on target at every dose we tested. And similarly, both compounds exceeded the dual combination at every dose we tested accept the lowest doses. So there was -- you could have picked either one of these compounds to advance as both an add-on and the dual. But when we really started to pull apart the PK, what we started to see was there's some unique differentiation between the two compounds that we think we can leverage in a way that best supports that clinical strategy. And so we picked 719 as the add-on really because at the lower doses of 719.

719 is a little bit more potent than 451 and we knew that, but where it really manifested itself was at these lower doses. We got higher exposure at lower doses of 719 relative to the target. So we got higher above the target with 719 as an add-on at the lower doses than we did at 451. So even though 451 exceeded that target, 719 exceeded it by more. And so we felt like why would we not pick the best compound for the add-on at the lowest doses that are going to drive the highest efficacy, it really was the best option we had for the add-on.

The converse of that is when we looked at the dual combination. 451 actually achieved higher exposure at the highest doses we tested relative to 79. And so we got higher above the dual combination target with 451 than we did with 719. And so again, we really tried to pick the best compound that would best support the individual paths as opposed to feeling like, well, we just need to pick one, we just need to pick one compound and advance them. So we really leverage those unique PK profile differences and I'd say the added benefit of that, just from a strategic optionality perspective, having two different compounds advancing 719 is the add-on and 451 as the dual combination.

It does create a lot of flexibility for us as to how we think about positioning and advancing these compounds because as you referenced earlier, Geoff, our prioritized path is the dual combination and that add-on as of right now is meant to be a proof-of-concept study but that path as an add-on, we could continue that path beyond the proof of concept. If the data was positive, it's really more of a capital question. Can we raise enough capital to pursue both paths in parallel. And so we don't have to make that decision now. We want to see that Phase IIa data and then see what the capital markets are at, at that point. And if we have a positive study and the capital is there, that would absolutely be something we could consider doing and having these two different compounds going into different directions just gives us that optionality.

Yes. Let's talk about that a little bit. So 719, the timeline for data and then maybe -- and you guys view like what does success look like that maybe will inform your decision to raise capital and to go into a larger study?

Yes. Do you want to talk about the study, Charlotte and then what we're looking for?

Yes. Our goal, as Mike said, really was a proof of concept, proof of mechanism study. Efficient, we wanted to read out in a relatively short period of time. So we're able to leverage, you mentioned sweat chloride Clad, we're able to measure and leverage sweat chloride is primary activity readout of that. It's a 2-week study and a 2-way crossover. We can do that in -- we're well powered for at least a 10 millimole per liter change in sweat chloride with under 20 patients on top of stable TRIKAFTA. So that really is the bar. That 10 millimole per liter change in sweat chloride above and beyond TRIKAFTA is really our bar. And we think that, that would put us in a position to truly differentiate versus anything that's been shown versus standard of care and really then allow us to correlate back to our CFHBE assay. Yes.

In sort of the stability the patients on TRIKAFTA -- I'm assuming that they have to be on drug for an extended period and maybe they can't have a lot of sweat chloride variability from like time point? I just -- maybe help us with like kind of the lead into that.

Yes. So another nice thing about sweat chloride is it is pretty stable over time in general. So that you don't need to select all patients who have stable sweat chlorides in general. But we do have eligibility criteria for them to have been on a stable dose even before they start in the study. And then we also have a 2-week run-in period just so that we're absolutely sure we know exactly what their baseline is on TRIKAFTA. So we get to leverage a lot of the characteristics of that.

Just given your experience with these compounds, is there a direct correlation between whatever points of sweat chloride could translate to x points of FEV1? Is it -- if you had 10 or 20, does that mean like a 2 or 3 points of FEV1?

Yes. So you're right. Over the course -- again, if you look over the course of the modulators, there has been a really nice correlation at a population level, study level between improvements in sweat chloride and improvements in remarkably up to the current point that, that correlation has been remarkably linear. We weather that remains strictly linear from now on, all the way up to normal CFTR function, we hope to be the ones to probe that and to test that. But we're pretty confident based on the data that if we can improve sweat chloride CFTR function substantially. And for us, that's at least a 10 millimole per liter change in sweat chloride, we believe there is the opportunity to improve FEV1 as well along with that.

And what we've said, Geoff, is that 10, if we can deliver 10, we think that would equate to something like 3 points of FEV1 to your question, in the future, right? That proof-of-concept study is not an FEV1 study. Just given the way it's designed, it's really designed for sweat chloride. But if we hit that 10 millimole sweat chloride number, it would give us, again, that confidence that we will deliver FEV1 in the future, somewhere in that neighborhood of 3.

As Charlotte said, that's been the pattern when you look back over the approved modulators that if you get into that double-digit realm, you can start to see that correlation. When you're below that, when you're in sort of single digits of sweat chloride, sometimes it has shown FEV1 correlation and other times not, right, just equally as many times. So we want to be outside the noise. That's why we picked that 10 millimoles to be outside that noise and leverage the history of these modulators.

But we also know we've done research, right? We've talked to physicians, and we've asked them what is clinically meaningful benefit above the standard of care? What would be meaningful to you that would get you excited about a new option? And consistently, what comes back when we engage the community is 10 millimoles sweat chloride an improvement, but we also want to see incremental FEV1 improvement. And that 3 points, again, is where that clinically meaningful bar tends to get set. Anything above that, even better. We know if we deliver on that proof of concept at least 10 millimoles of sweat chloride, that is clinically meaningful and that would be a win.

I mean, CF drugs used to be approved on a 2% FEV1, right? So prior to Vertex. Let's talk a little bit about the dual combination. So just give us the time lines for maybe a proof of concept. What are -- maybe -- and also what are the challenges of developing that in the context of kind of accepted standard of care today?

Yes. So I'll let Charlotte talk about what that -- we're doing a healthy volunteer Phase I study right now with the dual combination that has been initiated to test the two different combinations, 451 plus 2222, which is a TMD1 corrector and then 451 in combination with 109, which is an ICL4 corrector. The design of that study really is meant to show that these two combinations are safe and well tolerated and that we get the PK profile or the exposure profile that we can map back into the CFHBE assay to know exactly how high up the curve we can get from an efficacy perspective.

So the goal, it is a healthy volunteer study. We'll be able to determine which of those two compounds or those two combinations that we would select to move forward. But I'll let Charlotte talk a little bit more about like what -- where will we go from there. So after we select the dual combination, how does that play out? What are some of the challenges?

Yes. So first, the next set of studies would be in people with CF. And one of the other nice things about the history of the approved modulators is that generally the healthy volunteer, healthy subject PK has translated very nicely into people with CF, allowing us to map back to that HBE assay.

So we -- our strategy, if you step back, really is to build a data set as incrementally. And so the -- obviously, our proof of concept, proof of mechanism Phase IIa study on top of TRIKAFTA is really feasible. Feasibility is very simple and straightforward and that no one has to come off their standard of care modulator. We do expect that as we -- and we expect that, that data set will really be important to help drive enthusiasm for the later-stage studies.

For the dual combination, there's a lot of study designs that we're contemplating and that are available to us. We expect that we'll be looking at something like a randomized switch study in order to do dual dose ranging as the next kind of general phase of development with the dual combination in people with CF.

Can you look -- OUS in areas maybe where Vertex is not well adopted or maybe not reimbursed. I mean because I think initially, there is a long -- you probably know this better than anyone, the hesitation from -- in the U.K., right? I mean there's a 3-year negotiation where everyone was jumping on clinical trials there because you had an identified population, but they weren't on drug. But that's less the case now, right?

Yes. So our -- we do believe -- first of all, we hear a lot of enthusiasm. Actually, perhaps -- we hear a lot of enthusiasm both in the U.S. and ex U.S. for alternatives and new things and certainly, things with improved efficacy. So the kinds of studies that we're talking about in CF, they're very -- they're like if a dual dose-ranging study with a dual combination would be something in the 200 patients range. So we think those are very achievable, especially if we're not looking at a strictly placebo-controlled study. So with the -- we don't think we have to go into fringy areas. We think the major areas like the U.K. and the U.S. and Europe where CF research is so well organized, and we -- again, we hear such enthusiasm. We think we can do that there.

And maybe at a higher level, where do the assets from AbbVie and Galapagos fall into your priority list?

Yes. So as you recall, we in-licensed three compounds from AbbVie last year. We're very pleased to in-license those assets. They had clinical data, two of the compounds that we in-licensed galicaftor, which is 2222 and navocaftor, which is 3067, a potentiator both had Phase II data in combination, they had dual data combination or dual combination data for both of those compounds. So we knew they were very active Phase II data, well tolerated. So we're very pleased to be able to in-license some of them. We in-licensed 2851, another TMD1 corrector that had Phase I data.

So we really had an opportunity. AbbVie had many assets in their portfolio. We selected the best ones that we felt fit nicely into our portfolio as, one, great combination assets with NBD1, because remember, we only need one other complementary mechanism to combine with NBD1 to potentially get to wild-type levels of CFTR function, fully normal CFTR function.

So what we wanted to do by bringing those three clinical stage assets into our portfolio, it really gave us more breadth to the complementary mechanism strategy. We had multiple NBD1 shots on goal. At the time we did the AbbVie deal, we really only had 1 other clinical asset, which was our own SION-109. So by bringing those three assets in from AbbVie, it really gave us multiple options to see which one ultimately we thought would pair the best with our NBD1 compounds. The one we have selected to prioritize is 2222, galicaftor, the TMD1 corrector. That is now in that Phase I healthy volunteer study that I said in combination with 451. And when we look at our preclinical assay data in combinations with 451 and 2222, it's very compelling, right? We have an opportunity, again, with 2222 to potentially get all the way up into wild-type levels of CFTR function in that dual combination.

We also have that opportunity with our own 109 compound when we combine with 451, which is why we put both of them into that Phase I healthy volunteer study to help us select which one that we ultimately think can be successful. But the fact that galicaftor has Phase II data that the safety and tolerability is well characterized, it actually showed efficacy in CF patients as a single agent and as a dual combination, both in terms of sweat chloride and FEV1. So we really like that asset. And then financially, we structured it in such a way, it was a very compelling financial opportunity and a financial deal for us as well.

So really just added breadth and depth to our pipeline, really helped us put that combination strategy together in a way now that we have multiple options to win there. So it was a really compelling deal.

And so the capital that you have now, though, you can develop both strategies, right? But then how do the assets that you in-licensed kind of fall into that in terms of the -- maybe the R&D spend?

Yes. Do you want to talk about that one?

Yes. So we ended Q3 with $325 million in cash and we have cash runway into 2028. That cash runway assumes that we prioritize our dual combination after the Phase IIa proof of concept and go to the Phase IIb dose ranging with the dual Charlotte was walking us through.

As we think about some of our other pipeline assets that are not in the -- either the 719 the add-on, or two duals, that we're evaluating right now with 451. Those are opportunities for us for life cycle development down the road. We're very confident in the compounds we're advancing now, but we always want to be in a position where we can continue to innovate in the future. So that's how we think about those and the priority in our pipeline.

Would you say that in-licensing more compounds is maybe less of a priority? You just have to figure out the assets that you have today and the...

Yes, it's a great question. I'd say it's interesting, right? We were -- the AbbVie deal was perfect, right? It made perfect sense for us strategically to in-license that right down the sweet spot of our strategy, right, adding complementary mechanisms for the reasons that I said AbbVie was a great partner and it was a really well structured deal for us and for AbbVie. So that one made all the sense in the world.

I would say that we are a natural home for anything that's sort of in the CF space, right? And we will always listen and look for new compelling assets that are out there. We have a great franchise that exists today that we can continue to go with what we have and feel very strongly that we have a compelling opportunity to positively disrupt the CF landscape. But we do get inbound calls on other assets tangential to CF, what we're really doing now is we want to be hyper focused, right? We want to stay hyper focused. We have the capital to pursue what we're doing. We are open to other BD opportunities, but it would really have to be highly compelling. The bar would be really high because again, we have a great franchise right now that we don't necessarily need to add to, but you never close doors if something came across opportunistically that looked really good.

And but in the future, I think this is also one of your questions. Like right now, we are CF-only right? We are hyper focused on CF and our strategy. When we think out into the future and would we expand into other rare diseases or respiratory in some other way, those are all strategic questions we will address as we make further advancements in Sionna past the proof-of-concept data, show that we've got a demonstrated path in CF, we would be open to looking at different areas. We have a great team that has worked in larger markets, larger companies with different backgrounds. So our team is absolutely capable of expanding to new therapeutic areas, but the time right now is to focus on CF and deliver on what we can.

In CF, would there be any emphasis? So Mike, on adding drugs for ex mutation, premature stop? I know that, that's a different mechanism, not NBD1 related and there's a whole like cats and dogs of technologies that have used in that. It's been not easy, right, of a population..

Exactly. I mean like gene therapy, things like that, right? There's other ways of approaching CF. I'd say right now, our core strategy is the F508del patient population, right, and really deliver meaningful improvement to those patients. Again, in time, it could an adjacency be these other mutations, other mechanisms that might help us address the 10% of the patient population for which we can approach that would absolutely be something to think about strategically as a near-term adjacency to what we're already doing. But right now, I'd say our goal is execution, stay highly focused on what's in front of us, deliver that data in mid-'26. And then if we're successful, that opens up a different level of strategic conversations that you can have.

Makes sense. Let me ask you just about the economics of it, right? So the comment we always hear is all these drugs are expensive to begin with. So if you can improve FEV1 on the back of a $250,000 therapy, right? So what does the value of that? Like have you guys done any payer studies or things like that, what does that mean to eventually a patient outcome or it's not just quality of life, right? I mean legitimately like you're improving the pathophysiology of disease.

Do you want to talk little about the add-on approach versus the pool?

Yes. So there's two different pricing models, right? If we have our own dual, we're not adding on to the existing modulators, right? So there we can think about, depending on what our product profile is, you can think about pricing at parity or at a premium depending on where we deliver efficacy. So that's I think, very pretty straightforward.

As we think about a potential add-on, we're early in the payer research, where we've looked most is at comps from other markets where there's been underlying therapies and then you add on an additional therapy that further improves outcomes. And so there, what we see from other therapeutic categories is -- and even in with some more expensive base therapies is something like 25% to 40% premium above and beyond the base therapy for an add-on. And so that's sort of the range that we think about today. But obviously, as we have more data, we'll probe further with payers and look at what that could look like further if we were again to pursue that commercially because our primary prior to this path, as we've talked about, is the dual.

Yes. The dual.

I'd say - yes. And the North Star, Geoff, as you know, I mean, it's always about patient access, right? So when you think about your pricing strategy, we'll do all the work to engage the payers around willingness to pay and product profiles look like this, how do we start to think about the pricing strategy. The North Star has to be, how do we ensure maximum patient access, right? And pricing has to feed into that so that you're ensuring you're in a good place for patients, they have access to something that we think could be very beneficial to them. So if you start there, we'll do the work to inform exactly where we think the pricing will be as -- especially as our target product profile becomes more and more clear with more data, it's easier to engage the payers with kind of real data in hand.

Right. Yes. It does seem like when you look OUS or our geographies, U.S., Western Europe, Australia or the kind of the core Vertex markets, but there are many others you don't hear anything about Eastern Europe, Middle East, like South America, Latin America overall. Like so there are pockets of, I think, around the globe where this is truly a global market, probably ex Asia. But my point is that like there are many avenues you could -- there are many different payer discussions you have depending on where you are in the economic spectrum.

Yes. That's right.

So I guess the follow-on to that is that, okay, if you look forward into -- I know -- I mean, Charlotte did me a Phase III, let's get to the proof of concept first but when you start to think about how that could -- what would be the theoretical design of that. That's probably maybe in the back of people's mind, like, all right, like that's not an easy trial to run, but it could be something where if you had a strong argument and a proof of concept to switch for a much -- for a step-up in therapy then that would be a very straightforward trial to run. So I guess, obviously, data-dependent. But get your perspective on maybe what would a pivotal down the road looks like.

Yes. So obviously, I agree. It's early days, and we'll be having -- with data in hand, we'll be having conversations with regulators, which will be really important. We do -- again, we hear a lot of enthusiasm for it. First of all, it's a rare disease space and their regulators have worked with sponsors in this space and it's -- we expect to have partnerships with appropriately. I think ultimately, there are a number of what we consider very feasible possible registration study designs. Our goal, just keep reiterating, our goal will be, first of all, to be data-driven, but our goal will be to demonstrate improved efficacy. And once you have that as your possibility that opens up a lot of study design options, discussions. And so we -- if we -- if the drugs play out as we expect, we expect that there will be a very feasible, frankly, probably pretty straightforward path.

Yes. Maybe, Charlotte, talk too about the TDN and the relations with the CF? The cystic fibrosis foundation is a very important partner in CF, right, for us specifically, but given what exists today and where we think -- how we leverage that relationship?

Yes. Actually, it's been one of the real advantages or sort of joys, I will say, of working in cystic fibrosis is the TDN, the therapeutics development network run by the CF Foundation is really the gold standard for a highly organized, well-funded research network where all the -- most of the patients, the vast majority of patients are well known. They're well known to the researchers, and we get to leverage that our Phase IIa proof of concept has been endorsed or sanctioned by the therapeutics development network, which means we are able to leverage that network. And there are similar networks around the globe as well in the major areas of CF research. So we get to leverage that and work with deeply in those partnerships. So we think that is really kind of the wind at our back in terms of conducting any of these studies. We don't have to go find the patients and the quality of the researcher networks and the ability for them to know their patients well and identify appropriate patients is just extremely high.

Right. And if you go back to the proof of concept studies, Mike, I mean, are you -- you're pretty confident in the predictability. I guess you mentioned the HBE assays, I think, for Vertex that was the -- so the [indiscernible] frequency assay was predictive of clinical but then HPE was predictive of that. So are you pretty confident in what you have that could predict good proof of concept data?

We are -- yes, the CFHBE assay is really a great tool. It is the gold standard in vitro assay, right, that has been demonstrated to be clinically predictive. And as you probably know, it was created by academics, right? And it was honed by industry, Vertex, us and others. We've been running the assay for 15 years. We've got a lot of great data in the assay, including we've synthesized the VERTEX compounds in our assay. We've compared our assay results to the clinical results, and they match. We've got a lot of interface with public domain information of how Vertex runs their assay. We run it very similar to the way that Vertex does. The CFF is a great partner. We collaborate with them and understand that we run the assay the same way that they do. We run the same assumptions that they do. So we have a lot of -- we've tried to validate every which way we can with our assay. And so we have a high degree of confidence and the predictions that the assay is making shows us that we have an opportunity to do something very, very unique.

But what the assay is making is a projection, right? It's projecting based on if you hit certain exposure levels and thresholds, this is what the efficacy you can drive. What the Phase I data told us is we are hitting those exposure levels and exceeding them. And so we have a real opportunity to meaningfully raise the efficacy bar within CF. And that proof-of-concept study is the first opportunity we have to demonstrate what our prediction was in the assay and how did that translate to CF patients. And we've set that bar again, that 10 millimolar sweat chloride bar we've set is the minimum. That's where we start clinically meaningful benefit, but we also think there's potential we could push beyond that, but we know what success looks like. Success is at least that 10 millimoles anything beyond that is even just better. And the assay gives us a lot of confidence that we can deliver on that based on what we're seeing in the Phase I and how this will project forward.

And as you move to Phase II and then eventually Phase III, are there disease sort of biomarkers that maybe Vertex didn't look at that you could add? I'm just trying to think of like how you could further differentiate yourself to present the best efficacy. It's not just about FEV1 and sweat chloride, there are other pathophysiology kind of markers?

Yes. So we'll be looking broadly at anything that's appropriate to include in study design. There -- you're right, there may be gastrointestinal differentiators, who knows, but we'll be following the data.

I would say we are laser-focused on improving efficacy in general. And right now, we actually see significant room based on the population data significant room to improve the things that are known. And that is chiefly FEV1, sweat chloride, CFTR function and then all of the other things generally in longer-term studies that follow from that. So we'll look for anything and we'll be very eyes wide open. But at this point, we actually don't think we need to go way outside of what has been -- the markers that are important and demonstrate clinically meaningful benefit, we think there's a lot of room to improve those.

Okay. Guys, thank you very much. Great conversation.

Thanks, Geoff. Great to see you.

Well, welcome, guys. Before we start, I'm just going to read a brief disclaimer. For important disclosures, please see the Morgan Stanley research disclosure website at morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

So with that, Mike, Charlotte, Elena, been quite a year from successfully completing your IPO to announcing initial clinical data on two programs, which we'll get into in a little bit.

Maybe just to start us off, perhaps you can provide just a brief introduction on Sionna for those who may not be as familiar with you.

Yes. Great. Ben, thank you very much, and thanks, Morgan Stanley, for inviting us today. It's a pleasure to be with you, and thanks, everybody, for joining today. So I'm Mike Cloonan, I'm the CEO.

Just a quick background on Sionna for those of you who don't know. So we are focused on cystic fibrosis. We have a very unique opportunity that we're going after, a target called NBD1, which I'm sure we'll talk about later in the discussion today. With that target and with our approach that we're doing around combination therapy, most specifically a dual combination, our goal is to transform the standard of care in CF and to get more patients to normal CFTR function, which we'll talk more about the unmet need and how that plays in today's market.

But it's also important, not only given what our mission is and what we have the opportunity, to think back of where this story originated. So we spun out of Sanofi back in 2019, but the science goes all the way back to Genzyme. So this is a 15-year, in the making, program, research and development effort, and we wouldn't be where we are today hitting this very challenging target without the level of investments and the commitment that was made over that 15 years.

And the reason I say that is we often get asked, "How did Sionna crack this target?" And it wasn't just Sionna, right? It was the level of investment, the perseverance, the strategy that took place between really three companies. And as you said, we're in a very fortunate position with a lot of exciting things that have happened and are on the horizon in the next 6 to 12 months. So excited to share the rest of the story today.

Well, thanks, Mike. And yes, the long-tenured investment is obviously starting to pay dividends. So that's great. So you mentioned it briefly, but maybe you could just talk a little bit more about the opportunity you see in targeting NBD1 in CF patients.

Yes. So let's start maybe just with the size and what the unmet need is. And so the size of this market, as many people know, CF is dominated by one player, Vertex. They've done a very good job, obviously, developing medicines to help patients, but we see an opportunity to solve some of the unmet need that continues to exist in CF.

And that you can define that by quality of life, life expectancy. But one of the things that we are very focused on, as I mentioned, is getting more patients to normal CFTR function, normal protein function. Only 1/3 of patients today that are on the standard of care get to normal CFTR function. So that leaves 2/3 not at normal, but there really is an opportunity to drive more from there. And Charlotte can talk maybe later about what that actually means, getting more patients to normal CFTR function.

And the way, as I said, one of the key parts of our strategy is focusing on NBD1. This is not a new target. This is a target that has been studied for many years. The biology is well understood. NBD1 is a region or a domain of the CFTR protein that has not previously been targeted in terms of hitting that target.

But what NBD1? Why it's so important biologically? It is the #1 genetic mutation that causes CF is F508del. Approximately 85% of patients have a form of F508del. That mutation resides within the NBD1 region or domain of the protein. And what the mutation does is it causes NBD1 to irreversibly unfold at body temperature. So it's creating this instability in the NBD1 region, therefore, crippling the folding of the protein, the traffic into the cell surface and its overall functionality. So NBD1 is critical to a fully functioning CFTR protein and a normal CFTR protein.

We have the opportunity with our two stabilizers, 451 and 719 to do something very, very different. And we know that if you can stabilize NBD1, you can drive significant improvement in CFTR function. And for us, if you can stabilize NBD1 and then just correct one other part of the protein, you have the ability to deliver wild-type levels of CFTR function.

Got it. Yes, tremendous opportunity. I think you mentioned kind of 1/3, 2/3 -- I mean, how many patients is that actually in terms of numbers?

Charlotte, do you want to talk about patients?

Yes. So worldwide, there's over 100,000 patients with CF, although it is a rare disease, it's a large, rare disease. In the U.S., that's upwards of 35,000 patients. So you do the math, 80%, 90% -- 85%, 90% of them have at least one F508del. So it's a substantial number.

Sure. Definitely, no -- definitely a large patient population, especially for rare disease and a well-defined one at that. So you briefly mentioned it, Mike, about kind of the combinations and your multiple programs. So maybe you can just talk about the different strategies you have to improve the outcome of CF patients.

Yes. So we -- as we saw -- one of the most recent announcements we had now a couple of months ago was we're going to advance both 719 and 451, our two NBD1 stabilizers. And we were very pleased with that Phase I data because both compounds exceeded our profile that we had set going into the Phase I. And that profile was defined by PK or exposure targets that are derived from our CFHBE assay, which we may get into a little bit later, and also the tolerability, both compounds very well tolerated.

So we have this unique opportunity with two advanceable compounds to determine the strategy that would make the most sense for us that could leverage the differentiated profile of each compound, but that would also best support the development plan.

So our prioritized path, as I mentioned before, is a proprietary dual combination, right? The standard of care today is a triple combination. Trikafta is a triple combination, three drugs that come together. We are going after a double, so two compounds that could end up driving more clinical benefit than the standard of care.

And so NBD1 is the foundation of that dual proprietary combination that I'm talking about. And in this case, we're going to advance 451 as the anchor to that dual combination. We're going to leverage 719 as our add-on to standard-of-care, proof-of-concept compound. And Charlotte will get into that in a minute in terms of what that proof of concept is designed to do.

But we have two different compounds advancing in two different directions. 719 is the add-on to standard of care, proof-of-concept study. 451 is the anchor to the dual combination, and it really provides a lot of strategic optionality for us.

Our prioritized path, the one that we are funding, is the dual combination. We will be data-driven when we get the output of that proof-of-concept study as to what we would do with the add-on. But it really does enable us to have strategic optionality.

Definitely -- it's definitely an interesting decision to progress both and something that we've seen before in other trials and other companies as well. So it makes a lot of sense.

You mentioned it briefly, but I guess in the Phase I trials, I guess, how do the PK data that you observed kind of translate to maybe -- or demonstrate what you anticipated with your preclinical [ assays ]?

Yes. Charlotte?

Yes. So as you probably know, we run this cystic fibrosis HBE assay, which has been very predictive. And we -- certainly in Vertex' hands, and we run it in a way that's very, very similar according to all the published data from Vertex.

And when we track back in our CFHBE assay, we track back to where we would predict the exposure, would be the -- -- the threshold or the zone of exposure, would be targeted to exceed the CFTR function and hence, the lung function and clinical benefit. We are -- that's the zone that we're targeting, either, as Mike said, in the 719 add-on scenario and then in the 451 dual combination scenario.

So we have hit and exceeded both of those targets for both 719 and 451. So that's the zone, either in the dual combination or in that proof of concept that we're zeroed in on, and we've seen that in the first parts of the Phase I, and that's what we're targeting.

Got it. Nice, as Mike noted, to have the optionality with both programs. So kudos to you guys. Maybe we can drill into a little bit on the trial design for 719 in your Phase IIa. If you could just provide additional detail there?

Yes. So the proof-of-concept trial will be taking patients -- enrolling patients who are already stable on physician-prescribed Trikafta. And then in a 2-way crossover design, which allows us to be super-efficient, we'll give them 2 weeks, each of those patients, 2 weeks of both 719 and then they'll get the other placebo. And so we'll have a comparison of the sweat chloride, which is the clinical biomarker of CFTR function. We have the comparison of their sweat chloride when they're not -- when they're just on Trikafta, versus when they're on Trikafta plus 719.

And that we intend to demonstrate quite clearly, the unique mechanism of NBD1. So we know from our preclinical assays that NBD1 does something, as Mike said, very different in addition to and from the standard of care. So we'll be looking at that change in sweat chloride or expected improvement in sweat chloride.

And it also will allow us then to be able to correlate back to our CFHBE assay predictions, and then we also expect to demonstrate that when patients are stable on Trikafta, that there's still a lot of room to go in terms of improving CFTR function. So it hits a lot of the proof points for us.

Got it.

Maybe, Ben, just one thing to elaborate on what Charlotte said, why that's so important, that proof of biology, right? As you go back to NBD1 and its role, none of the approved modulators today from Vertex stabilized NBD1 directly, right? So -- and the way they're solving the protein is they're partially correcting the protein. We're trying to get to full correction of the CFTR protein. And as Charlotte said, by showing that sweat chloride improvement and improvement in CFTR function, it's going to demonstrate that NBD1 is synergistic with but different from components of Trikafta.

Got it. Got it. Makes a lot of sense. I guess maybe a follow-up question to that on maybe just the trial design in my head on this. But I know there's a washout period in the trial, which I found particularly interesting. If you could just maybe talk about that? And maybe that it's going to help with some of the measurements in this clinical trial?

Yes, the washout is just because this is a 2-way crossover study. So each patient enrolled in the trial will get both the placebo and the 719. And in order to -- and of course, they're going to be randomized to either get one of those or the other first.

And so they stay on their Trikafta throughout the entire trial, but then whichever thing they get first, be it placebo or 719, then we have a period where they're washed out from whatever that -- obviously, the placebo doesn't really require a washout, but they don't know it. And we just -- we'd want to make sure that whatever change in sweat chloride has occurred, really from the 719 portion, is back to baseline by the time we do the second period. So it's a very common design element in the two-way crossover study.

Got it. Makes sense. Thank you. You mentioned the sweat chloride measurements. I guess what other data points can we expect to see from the trial?

So we'll be looking definitely at safety and tolerability as well as PK. So those are really -- that's really going to be the suite of this.

Well, maybe we can talk about -- and we had asked a lot about FEV1, right?

Yes, yes.

So why not FEV1 in this study? And it's not designed for that. [ I mean ], Charlotte, just explain why it's not FEV1.

Right. Because we can leverage sweat chloride and the efficiency and the speed of sweat chloride change, we're really -- we can do a very small study, with less than 20 patients in this -- and also leveraging the two-way crossover study design. And that really is just not powered at all for demonstrating an impact on FEV1. We'll be assessing it as a safety endpoint. But it's really -- in order to really do an FEV1-based study, which for -- certainly for the dual combination and if we were to go forward, with the add-on, we would be doing that in the later Phase II.

Got it.

Yes. And we do believe NBD1 in our programs will drive FEV1 improvements, right? We're focused on sweat chloride, and that's the design of this proof-of-concept study. But when you think about dose-ranging Phase III parts of the clinical strategy, FEV1 will absolutely be part of that, and we believe we will improve FEV1 with NBD1.

Got it. Makes sense. And then I guess maybe just the last question on the trial. I guess, when should we expect to see data?

Yes. Elena, do you want to take that one?

Yes. So we'll have data from the study mid-2026, so mid next year.

Got it. All right, thank you. Well, obviously, I don't want to forget about 451. So maybe we'll have a similar conversation about it. Would just love to hear -- you touched on it, but just the decision to combine 451 with your proprietary program.

Yes. Maybe we didn't get into this yet, so it's probably worth stepping back with the Phase I data, what specifically drove us to this path of 719 one way and 451 the other? So as Charlotte said, both compounds exceeded both of the targets we had set, the add-on target and the dual combination target.

So we could have picked either one of these compounds to advance. But when we looked at it, there were actually some unique PK profile differences between 719 and 451. And specifically with 451 since we're [ segmenting ] there, 451 achieved higher levels of exposure than 719, at the highest doses we tested. So they weren't apples-to-apples doses of 451 and 719, but at the highest doses tested for each compound, 451 got higher exposure.

And that's important when we think about the dual combination because with the dual combination, it is what it sounds like. It's two compounds coming together, one of which is NBD1. And then we're going to be testing that with two of our complementary mechanisms, SION-109, which is an ICL4 corrector and SION-2222, which is a TMD1 corrector.

And that higher exposure that we're achieving at the higher doses enables us to drive, as per the HBE assay, higher levels of clinical benefit. And that's really important, right?

In our own combination, now we're trying to drive improvement above the standard of care. We're not having the benefit of adding it to the standard of care. We're going directly against the standard-of-care. And so to achieve superiority, the higher exposure we can achieve with the NBD1 compound, the better to be able to deliver that efficacy that we seek. So that makes sense?

Yes.

So I'll let Charlotte describe what we're going to do now in terms of the healthy-volunteer combination.

Yes. So we've tested both -- actually, we're taking two 451, together with two complementary modulators, two interface domain correctors, Galicaftor, which we obtained from AbbVie, which had already actually been in Phase II. And then our own internally developed SION-109. Galicaftor is a TMD1-focused corrector. 109 is an ICL4 corrector.

And so -- and ICL4 has been through a full Phase I study of its own, single agent, as has 451. So we have solid -- for [ one up ] to Phase II data, but solid, [ say ], at least Phase I data for all of them. And now we're going to take 451 and Galicaftor and 451 and 109, and we're going to put them together in sequential cohorts of healthy volunteers to look for safety, tolerability and really zone in on those PK zones that we talked about from the CFHBE assay that we clearly hit in the single-agent studies, and we just want to confirm that we're in the same place together and that the safety and tolerability is as we expect also from the single-agent studies. And then decide from then which of these we'll take forward into Phase II in patients.

Got it. Makes sense.

And we did announce just over a week ago that study has started. It's a healthy volunteer study...

Yes. Well, congrats on that. Nice achievement for you guys. And I mean, I know there are well-known targets and mechanisms, but if you can maybe just talk about a little bit more on the rationale or role of ICL4 and TMD1 and the rationale for that combination?

Yes. Do you want to talk about how they work together?

Yes. So when -- if you can picture the CFTR protein with its multi-domains and NBD1 kind of the down in the corner, as Mike said, what F508 deletion actually does is not only cripple and unfold NBD1, but it also disrupts the interface domains. And so the whole protein as a whole doesn't assemble and then traffic and work correctly. And so ICL4 and TMD1 are -- they're both each two different interface domains. And so correcting -- we know from even data before there were modulators, we know that correcting just one of those interface domains together with NBD1 modulation or correction can achieve potentially wild-type CFTR function.

There isn't -- from a target perspective, when you look at TMD1 versus ICL4, either one of them combines really well with NBD1 and can get to that wild-type level of CFTR function that Charlotte is saying. So it's -- we're sort of agnostic to whichever target to go after. It's more the compound, right? So 2222 Galicaftor is TMD1, 109 is the ICL4. It's really going to be the performance of those compounds, not the target per se that we would select to combine with NBD1.

Got it. And maybe just following up on that. I mean, what will you look for in the Phase IIa that will drive the decision of moving one versus the other?

Well, it will be the Phase I healthy volunteer study that we're going to be doing, the Phase II [assay] -- 719, yes. So we'll be looking for -- actually all the things that we were looking for in the earlier Phase I, we'll be looking for safety, tolerability, and we had a very high ceiling for all of these compounds in that, and then also just where we can get in terms of the target concentration zones together in a combination.

Makes sense. And I think we touched on a little bit, but we mentioned the ability or the potential to achieve wild-type function. I guess why is that just so much more important than, let's call it, normalized function?

Yes. Well, it is normalized function. And you'll hear others in the field talking about achieving better CFTR function. There really hasn't been a tool to date before the NBD1 to -- at least based on the in vitro assays, really to drive into those substantial zones of normal.

If you look at the waves of improved CFTR modulators so far, they've moved patients sequentially to better and better CFTR function to the point where 1/3 of them now are in the normal range, but 2/3 of them aren't. And over those waves, as the CFTR function has gotten better, the outcomes have gotten better, both short term in terms of FEV1 and quality of life, but also long term, as Mike was alluding to, long-term outcomes, rejection in transplant, lifespan, survival. So that's sort of pointing an arrow right towards if -- there hasn't really been a tool to get us to that, but if you can, that shows us what you can potentially do.

Definitely. Yes. I mean we were talking about the patient populations earlier, so that would be pretty tremendous. And then I guess last question on this trial, but I guess when can we expect to see data from this as well?

Yes. So we'll have data from the study also mid next year.

Got it. So two trials reading out in mid '26. Is that right?

Yes.

Yes. Maybe, Elena, also talk about just what the next news flow -- like what will be the next [balance] -- we have that data mid-'26, but what do we expect?

Yes. So as we discussed, we've already initiated this combination Phase I healthy volunteer study that supports the dual combination. That data will report out mid next year. And then the next step with the dual combination will be to go into a Phase IIb dose-ranging study in patients with CF. On the add-on to standard of care, as we talked about, we'll have data from that study mid next year, and that study will initiate in the second half of this year.

Got it. Great. And it sounds like a lot going on. I guess, maybe just a question on kind of current cash position and cash runway.

Yes. So we ended the second quarter with $337 million in cash, which will take us into 2028. So extends us way beyond these next set of data milestones, 18 months plus post -- after data.

Got it. Great. Yes, I mean, fortunate to be in a cash position and kudos again on the IPO earlier this year that helped enable that. So that's great. I know I have a little bit of time left. But Mike, I don't know -- or Charlotte, Elena, is there anything else maybe you'd like to apply to [indiscernible]?

Yes. I mean just a couple of [things]. One is we're very excited about where we are. Great question from you, Ben, in terms of the progress of the company and the progress we made. We've executed at a very high level to put ourselves in this position, right, with this unique first-in-class mechanism NBD1, two different compounds progressing in two different directions. data catalysts coming within 12 months, as Elena said, in mid-2026.

The one thing we didn't spend maybe a second on was just -- we talked about the size in terms of the patient population, right, the 100,000 patients but the size of this market, right, how meaningful this could be to patients to have a new option with a new mechanism that could potentially be differentiated and maybe even best-in-class, right? And for us, this is an $11 billion market today, right? As we know, that, Vertex owns and dominates. It is growing to $15 billion in the near term. And what we know is as we go back to that unmet need of 2/3 of patients not being at normal, our focus has been on how do we deliver new potentially more efficacious options for patients, drive more of them into the normal CFTR function range. And we think that could be transformational for patients, but also a significant commercial opportunity for Sionna, when you think about that $11 billion going to $15 billion market with a single player.

Yes, definitely, large opportunity, especially potential for best-in-class. And always -- there's always been second -- second [entrants] to overthrow incumbents. So a lot of opportunity and potential there.

Agree.

Well, guys, thank you for the time.

Thank you, Ben.

Yes. Thanks for kicking off our conference here.

Pleasure.

And looking forward to catching up.

Thank you, Ben. See you around.

Thank you, guys.