Sionna Therapeutics, Inc. ($SION)

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.