Conference Transcript - SION 2026-06-10

Salveen Richter, Analyst — Goldman Sachs

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

Mike Clunan, CEO

Yeah, well, first, Selvien, thanks for having us. It's great to be here with you. Thank you, Goldman, for hosting us as well. And, yeah, 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 two different data readouts happening in the summer of 26. We have our Phase 2A proof-of-concept study, which is the precision CF study, where we are testing our 719 NBD-1 stabilizer on top of Trikafta in a sweat chloride-based study that really is meant to demonstrate that NBD-1 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 a FEV1 study per se, but this 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 CFHB 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 two other drugs in a two-drug combination. So we have 451 in combination with Gallocafter, which is Scion 2222, a TMD1 corrector, and we're also looking at 451 in combination with Scion 109, an ICL4 corrector. We'll have that data in the summer of 26, and that data is healthy volunteer phase one data, which will have PK slash exposure of the two drug combinations, as well as the safety and tolerability of those two drug combinations. and the goal of that data is to help us select which of the two 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 two strategic decisions that we have to make with those two 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 Siona and then we'd get into some of those timelines going forward. I want to jump into the program

Salveen Richter, Analyst — Goldman Sachs

before that. If you were to take the add-on forward, how would you translate from the add-on doses. You're at a lower dose now, and you're going to move forward with higher doses on the

Mike Clunan, CEO

board. Yes, I'll start, and then I'll let Cheryl talk to you 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 F508 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, Aleftrek, an adult homozygous patient population, they delivered about a 3 millimole sweat chloride, and they were non-inferior on FEV1 in their phase 3 studies. So we not only would we be above the Trikafta by that level, but a significant improvement beyond where Aleftrek 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 Aleftrek. And then if we make this 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 Aleftrek moving forward. And I'll let Cheryl just talk a little about what that next step could be.

Charlotte McKee, Board Member

Yeah, so the next step, again, if we were to move this forward, would be dose-ranging, and, you know, we would, as Mike said, you know, we'd be looking at the appropriate dose range. We have said, you've heard us say, you know, this add-on scenario in general both only needs a low dose or concentration of an MBD-1 stabilizer because of the power of that, you know, mechanism, and, you know, when we think broadly about the potential of embarking on an add-on program to standard of care, you know, there are many reasons why keeping that dose low has other advantages, you know, 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, we'd be driven by the data, you know, from the proof of concept and whatever dose range we were looking at in the next dose ranging study, you know, we would obviously be data-driven and have what we would consider an appropriate dose range to prepare us for phase three, for phase three dose ranging. And we would be looking, if we were to go into that next step, you know, we'd be looking at probably at least exploring both Trikafta and Aleftrek because mechanistically it's the same, you know, mechanisms.

Salveen Richter, Analyst — Goldman Sachs

ahead of the top line phase 2a 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 and speak to your confidence in actually achieving

Mike Clunan, CEO

this yes i'll i'll start with sort of um why we said it and what what's the context and the relativity of it then charlotte can actually speak to what is it what does a 10 millimolar 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 Alotrec? 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 achieve. 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 this 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 Aleftrek, right? And that we see that in the same patient population, this homozygous adult patient population, F508-DEL, they delivered around a three millimole sweat chloride, non-inferior on FEV1. So we look at that as now you have the options for Trikafta and Allotrec, and our goal has 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 2A precision study is sweat chloride based with the 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 continue 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 three percentage point improvement and 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 can strengthen. So that's the other reason why for us hitting the clinical meaningful bar is important. Also the confidence and the ability to then see FEV1 in the later stage studies increases and then the relative bar of both Trikaft and Allotrex. 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

Charlotte McKee, Board Member

that then translate to patients? Yeah, 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, you know, the lower the sweat chloride, the better the CFTR function, the better the short-term endpoints are, and that, you know, 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 in 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 you know 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

Mike Clunan, CEO

function. And interesting, it is consistent when you think about how Vertex is messaged, right? Every reduction in sweat chloride matters, right? Lower sweat chloride is better. And even as like Allotrex, sort of a modest three 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.

Salveen Richter, Analyst — Goldman Sachs

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

Mike Clunan, CEO

Yeah, 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 Aleftrek 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 Aleftrek 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 Alloftrac and Trikafta, we would expect to be similar because the mechanism is the same.

Salveen Richter, Analyst — Goldman Sachs

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?

Charlotte McKee, Board Member

We're very confident. I would say just for all the reasons that Mike, you know, alluded to before, it 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, you know, 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 know, you look across different mutation groups, those dynamics may be slightly different, you know, 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.

Salveen Richter, Analyst — Goldman Sachs

Great. At a high level, can you describe the patient's baseline characteristics here and how these will inform the study's outcome? And, you know, 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, you know, 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?

Charlotte McKee, Board Member

Yeah, so what we're trying to do, so this particular study, while we're very, you know, excited about the study, and it's going to answer some really important questions, it's not going to answer every single question, you know, 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 we are trying to run this right down the middle in terms of enrolling these patients. And we haven't, you know, described exactly the eligibility criteria, but you can imagine conceptually, if you just look at the range of 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 MBD1 stabilizer, but this is not the study for us to probe 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, you We're enrolling those patients who have gotten all the benefits they possibly can from Trikafta already. Stable on that, what else does NBD-1 stabilization do above and beyond that?

Mike Clunan, CEO

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 NBD-1 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 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 trials with 16

Salveen Richter, Analyst — Goldman Sachs

patients, do you think that the data will be pretty consistent across the patient group, and And do you plan to share patient data on an individual per patient basis?

Charlotte McKee, Board Member

Yeah, so exactly how, you know, we'll have top line data, you know, sometime this summer and exactly what level, you know, we share first versus in a medical, you know, meeting is, you know, 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, you know, we've built the potential for some variability into the powering and the study design. You know, so this will be, you know, we're expecting, like you've seen with every single modulator trial, there's going to be a range, right? But the, you know, what we're looking for is the mean change and, you know,

Mike Clunan, CEO

we're an expected variability. Yeah, 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 as 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 see that, but there's some extra

Salveen Richter, Analyst — Goldman Sachs

color and context we can provide. And while the Phase 2A 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.

Mike Clunan, CEO

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

Charlotte McKee, Board Member

So the next, you know, let's just take the potential add-on to standard of care. If we were taking that path forward, the next step would be dose ranging. And, you know, 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, you know, with the goal to identify clearly the kinds of dynamics that our drugs, you know, have with respectable sweat chloride and FEV1 that would allow us to then power a phase three 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'd know exactly what we would go into a Phase III study powered for.

Salveen Richter, Analyst — Goldman Sachs

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.

Mike Clunan, CEO

Yeah, 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 into, 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 learn 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 one 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 the thing we're going to base our selection of the two drug combinations on is going to be do we see any safety or tolerability separation in our two drug combinations and what's the efficacy potential of those two 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 two-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 two-drug strategy, the dual-combination strategy, that we will glean from the POC.

Salveen Richter, Analyst — Goldman Sachs

Do you think that you'll need to see data outside of the homozygous 508 DEL population to kind of fully validate the assay? Or do you think just this population alone could do that?

Charlotte McKee, Board Member

Yeah, 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 F5OIDL homozygous, you know, cells, because those are the most common, you know, genotype. And if you think about what you're testing with that, that's two versions of the F508-DEL allele. So all of the CFTR in that system is mutated F508-DEL CFTR. And so if you then take those data consistent with what's been shown for the approved modulators, You know, the next largest population by clear genotype is F508-DEL 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 up to 90% of people around the world have one copy of F508 DEL and then either the second copy of F508 DEL or something else on that other. So we absolutely believe with good reason and data that the F508-DEL homozygous CFHBE data are 100% applicable to other F508-DEL mutation, you know, heterozygous mutation groups. But also, we do do some, you know, a smaller amount of work in our CFHBE assay with, for example, FMF, you know, HBEs. So, we know what the, you know, different correlations and dynamics are, and they are all very applicable, you know, and comparable to the homozygous population.

Salveen Richter, Analyst — Goldman Sachs

Moving to your phase one 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 NBD-1 stabilizer 451 in combination with Gallicafter, so 2222, and 109 to decide which proprietary dual combination you want to advance into Phase II?

Mike Clunan, CEO

Yeah, so it's really, you know, we're testing two different two drug combinations, as you just articulated, Salvin, and the goal of that study is to generate enough data that is going to help us select which of those two 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 two 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've 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 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 CFHB assay to leverage. So as we get the PK and the exposure of the different doses we're testing of the two drug combinations, we can then put that back into the assay and determine where are we on the efficacy bar. And if one of the two 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 CFHB

Salveen Richter, Analyst — Goldman Sachs

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 a one-third of patients today. So this idea that if you're able to even lower chloride further, can you actually benefit those patients in that cured population?

Mike Clunan, CEO

Less than 30 more.

Charlotte McKee, Board Member

It's unknown. There haven't been enough of them studied over longer periods of time to know if, you know, a pharmacologically improved CFTR function below that bar of 30 is, you know, provides a benefit. So, you know, what we do know is lower is better. And 30 has been his, you know, it's been a cutoff based on epidemiology and diagnosis, et cetera. You know, I think it remains is an open question, but, you know, our goal, as Mike has said, is lower is better, and we're going to drive as low as, you know, as possible. So we, just to, you know, 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, you know, eligibility and CFTR function in later stage studies. And I would just say, so when you think about everything

Mike Clunan, CEO

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 one-third that are below 30, that unmet need is lower than what you'd say those two-thirds that are not yet at normal. So when you think about who can most benefit, we are sort of targeting that two-thirds that we think can really drive the most benefit. Maybe we can move more of them to the normal range, right? That would be the goal. And then, you know, as Cheryl 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

Salveen Richter, Analyst — Goldman Sachs

above 30. And going back to the dual combo program here, how do the complementary mechanisms of 109 and Gala-Caftor specifically?

Charlotte McKee, Board Member

Yeah, 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 Gala-Caftor or whether it's paired with our ICL-4 modulator, cyan-109, what really is left unaddressed by those two mechanisms is directly stabilizing MBD1. So no matter what the combination, the MBD1 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 Gallicafter or Sine109 each do, is enough to potentially improve the function to wild type.

Salveen Richter, Analyst — Goldman Sachs

I bet you can't wait for data to stop answering all these questions.

Mike Clunan, CEO

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, you know, 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 Siona is.

Salveen Richter, Analyst — Goldman Sachs

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

Mike Clunan, CEO

Thanks, Delvin. Always a pleasure.