All right, I think we are live now. Good afternoon, everyone. Welcome to Guggenheim Emerging Outlook Biotech Summit 2026. My name is Yatin Suneja, one of the biotech analysts here. It is my pleasure to welcome our next presenting company, Sionna Therapeutics. From the company, we have a few executives here who I will be having a discussion with. We have the Chief Executive Officer, Mike Cloonan, here. We have Charlotte McKee. She's the Chief Medical Officer, and then we also have the Chief Financial Officer, Elena Ridloff. Mike, why don't you make some opening comments? I think Sionna still is a younger company in a lot of investors' minds. Just tell us a little bit about the history, highlight some of the upcoming catalysts, and then I've prepared a few questions for you, for us to have a discussion.
Yeah, Yatin. First, thanks very much, Yatin, to you and the Guggenheim team for inviting us. Pleasure to be here with everyone today. I'll start just with the background, as Yatin just said on Sionna, but we are on a mission to revolutionize the treatment paradigm in CF, and we're gonna do that by leveraging our unique and first-in-class NBD1 stabilizers, which we'll get into later in the discussion today. And we're in this unique position to really positively disrupt this large market of CF that has been dominated by the one player, as many of you know. And but we wouldn't be where we are today with some of the history, as Yatin pointed out. The science behind our programs goes all the way back to Genzyme.
We originated over 15 years ago, and then the science continued into Sanofi post-merger, and then Sionna was formed back in late 2019 as a dedicated CF company that could take the science behind Genzyme and Sanofi's programs and accelerate them to where we are today, which is now we are in the clinic with multiple NBD1 programs and our complementary mechanisms that we're using in combination. When we look ahead, this is a very important year for Sionna, 2026. Middle of this year, we're expecting multiple data readouts and catalysts. One of them is our PreciSION- CF study, which is a phase 2a proof of concept where we are testing one of our NBD1 stabilizers, SION-719, on top of TRIKAFTA, the standard of care, in a 2a crossover study that is designed to show sweat chloride improvement when we add 719 to TRIKAFTA.
This is the first patient study with NBD1 that has been run, so it really gives us an opportunity to show that we can improve CFTR function over and above the standard of care. It will also show the first chance for us to show the translation of our CFHBE assay in CF patients, and we'll have that data in mid-2026, as I said, so a very important time frame for us. On the same path, we also have our second NBD1 stabilizer, SION-451, that we are in a healthy volunteer dual combination study where we're testing 451 in combination with two different complementary mechanisms. The first is SION-2222, which is a TMD1 corrector, and then we're also combining 451 with our own ICL4 corrector, SION-109.
That data we also expect to have in mid-2026, and what that data will show us is the combination tolerability of those two programs and also the PK profiles of the combinations. The goal is to select the best dual combination that we would progress after those studies read out in mid-2026. So very important time for us, but super excited about the potential that we have to add new, meaningful options for people living with CF where NBD1 is the foundation of what we're trying to accomplish.
Got it. So, Mike, the core to your thesis or the hypothesis is this NBD1 biology, right? So can you talk about what is unique about this target, why this has not been explored? Was it a biology question or more of a chemistry question, and how you might have resolved it?
Yeah, so let me, let me talk about the biology real quick of, of the CFTR protein, of which NBD1 is a, a part of that. So we know what causes CF. Genetic mutations to the CFTR gene impact the CFTR protein. There are different regions or domains of the protein. NBD1 is one of those regions. And what we know is that the number one genetic mutation that causes CF is F508del, as many of you may know. That impacts approximately 90% of patients that have CF, and that mutation resides within the NBD1 region of the CFTR protein. And so what the mutation does is it causes NBD1 to irreversibly unfold at body temperature. So it's creating this instability not only in NBD1 but in the CFTR protein. So it's crippling, it's folding, it's trafficking to the cell surface, and then it's overall functionality.
The current standard of care, TRIKAFTA, corrects around NBD1. It's correcting different parts of the protein but not directly stabilizing NBD1. And NBD1 is the thing that goes most wrong in the dysfunction of the CFTR protein as it relates to F508del. So the biology has been well understood around NBD1, its potential. If you can correct any part of the protein, you would start with NBD1. It creates the highest level of stability and correction of the protein. But to Yatin's question, the reason why nobody's been able to get to this point until Sionna has. The chemistry is very, very challenging. There are very shallow binding pockets that exist around NBD1, and there are companies who have tried to attack this biology.
One was Pfizer that wrote a paper about this back in 2016 where they took a long, hard run at NBD1, and what they concluded was this was an undruggable target because of the very shallow binding pockets. We also know more recently Vertex has said that they also tried to stabilize NBD1, but I think the words they chose was they could not optimize this target. So to their credit, they found other ways to correct the protein but not able to stabilize the thing that most goes wrong in NBD1. So it is a very challenging target, long considered undruggable, like I said, up until this point, but also was known to potentially be this holy grail in CFTR correction if you could drug it. And that's where we are today with our two NBD1 stabilizers that are in the clinic.
Okay. I think there's some new preclinical data that just came out which talks about if you stabilize NBD1, you can actually restore the half-life. Can you just touch?
Absolutely. Yeah, Charlotte, you wanna take that one?
What is the relevance of that?
Yeah, so it's just yet another piece to, you know, what we see as the puzzle. So, F508del, the protein F508del CFTR has a number of different things that go wrong. You know, Mike talked about the folding in the assembly, and then part of what that means is that then there's very little of it that gets through the protein, you know, quality control machinery to the cell surface. But then also what protein, F508del CFTR protein, gets to the cell surface has a much reduced half-life. You know, it just it gets turned over much more quickly than normal.
And as we, you know, we sort of suspected that, you know, based on kind of the stability and sort of what we see preclinically when our researchers stabilize F508del CFTR with NBD1 stabilizers, we suspected that there might be an impact on the half-life as well. But they just recently, it's a complex set of assays to show that. And so we just recently presented it at the North American CF Conference, data showing, you know, through very elegant pulse chase experiments that with NBD1 stabilizers, either on their own or in combination with any of the, you know, current mechanisms, complementary mechanisms, that CFTR protein half-life can be restored to normal wild-type range.
Got it. And then how much of a help do we need with other add-on CFTR modulators? So obviously NBD is one part of the puzzle, right? But you're using other, like, how—what is the synergistic benefit?
So our strategy has been to develop a dual combination, two compounds coming together of which NBD1 is the anchor compound because of the amount of correction it creates in the protein individually. No other corrector or stabilizer can do what NBD1 can as an individual compound. But to your question, Yatin, to if we wanna get to fully normal CFTR function, as Charlotte is alluding to, wild-type levels of CFTR function, we need one other compound to combine with NBD1. Because as much work as NBD1 can do to stabilize and correct the protein, we need one other part of the protein to be stabilized, mainly because of the interdomain assembly defect that happens also as a result of F508del.
There are other things that need to be corrected in addition to NBD1, but we have the potential to do something that no one else to date has been able to, which is create a dual combination, two drugs that have the potential to deliver fully normal CFTR function.
Got it. So let's talk about the clinical development. Obviously you've gone through the DDI studies, you have gone through healthy volunteer studies, so you don't need to recap the data, but maybe we'll just focus on the phase 2a PreciSION study. Yatin, walk us through the study design. It's like a crossover study. What exactly are you trying to achieve? What type of patients are you gonna get? What should we be looking for when you announce the data?
Yeah, so I'll start. So this is a sweat chloride-based study. It's designed really to address three main points, you know. One is it's designed to show that NBD1 stabilization does something unique, mechanistically unique, and differentiated from the standard of care. It's also designed to show that, you know, if the data play out as we expect, that there is substantial more CFTR function still to be derived, you know, by adding NBD1 stabilization above and beyond the current modulators. And then it will also be the first place that we're directly translating our own CFHBE preclinical assay into outcomes in people with CF. So sweat chloride is, of course, the biomarker, clinical biomarker of CFTR function.
So it is a 2-week dosing period paradigm in F508del homozygous patients who, and we have enrolled patients or we have eligibility criteria that define what we consider a sweet spot in terms of the dynamic range and sort of the, you know, we're looking for kind of the right down the middle F508del patients who are already stable on their physician-prescribed TRIKAFTA. That stays throughout the entire study, but with that background, then the patients will have two 2-week periods in that we don't know who will start with what first, where they'll get either TRIKAFTA, their TRIKAFTA plus 719 in a lower dose range, and TRIKAFTA plus placebo. And so the readout will be the sweat chloride change, you know, at the end of that, basically a 2-week dosing period.
Each patient serves as their own control, and the study is powered for at least a 10 millimole per liter change in sweat chloride above and beyond their baseline. We chose that because that really has been both, you know, kind of the historical benchmark, but really is what, you know, we continue to hear would be the beginning of clinically meaningful for.
Got it. So we'll come back to that threshold in a little bit. Just let's address the patient population. So you just touched on that you are only going after homozygous. Why? How should we think about their baseline sweat chloride level? Just really put in context these patients for us, like.
Yeah, so this is a, you know, proof of concept study. So we wanted to make this as clear-cut and as, you know, unconfounded as possible. So obviously F508del homozygous patients is the largest genotype subgroup, but also that's we get the it is a homogeneous genotype, so that takes out that variability of genotype. Obviously with our NBD1 stabilizers, long-term we are interested in providing a potential, you know, potential options for anyone with an F508del mutation, but this is the first proof of concept population. And we are, again, we know from real-world data sort of what the range of baseline sweat chloride values/CFTR function values are in patients, these patients on TRIKAFTA. So we've chosen the middle of that range, not yet normal on TRIKAFTA, but not, you know, not patients who have had absolutely no benefit on TRIKAFTA.
Okay. So they have room to improve basically now and more homogenized patient population.
Yeah, and to Charlotte's point, Yatin, I mean, the goal, again, this is a small study, 16-patient proof of concept study. The goal is to have as broad a label as possible. If we get to commercialization, where we would have homozygous and heterozygous, appropriate age groups, and really give ourselves an opportunity to reach as many patients as possible. 'Cause again, the goal for us is to drive as many patients to normal CFTR function as possible. Today, only a third of patients get to that normal level on both TRIKAFTA and ALYFTREK.
Got it. Obviously the goal is Sweat Chloride level. How quickly Sweat Chloride levels change? I think there is a 28-day washout. Is that enough to sort of capture the decline and then going back up? Yeah.
Yeah, good question. So sweat one of the, like, Sweat Chloride is just really an incredibly useful biomarker of CFTR function. It can change very rapidly within hours to days. And so we do believe that, that 14 days, two weeks is really long enough to see the kinds of changes that we're looking for. That washout in the middle, again, everyone stays on their TRIKAFTA, that washout in the middle we think is, is absolutely long enough. It's obviously only really necessary for those patients who started on 719. It's really an NBD1 washout, but because it's randomized and double-blind, you know, the patients who start on placebo have to go through the washout too. But yes, we think that's long enough.
Got it. And then, 10 millimole, like, that's the question I have everybody's trying to get a hands-on. I'm like, why 10? Why not eight? Why not 12?
Yeah, yeah, I'll start and Charlotte can chime in. So it really comes from a couple different dimensions. Charlotte referenced one of these before, which is where does clinically meaningful start? If you talk to the community and ask them what is meaningful improvement above that standard of care, that 10 millimoles of sweat chloride is meaningfully different from the standard of care. That's about a 20%-25% improvement just as a reference point versus, say, a TRIKAFTA. And that's typically what you'll hear. If you talk to the community, you'll hear that consistently. That's where the bar starts for clinically meaningful improvement above and beyond the standard of care.
In addition, there's also an implied assumption that if you can drive 10 millimoles of sweat chloride improvement, you'll also see FEV1 improvement, something in the order of three percentage point improvement of FEV1 if you can drive that level. So that's where we started, right? We wanted to create clinically meaningful benefit above the standard of care, first on sweat chloride. If we can drive that level of sweat chloride, we believe we'll be able to drive FEV1 improvements. That PreciSION CF study is a sweat chloride study. It's not meant to show FEV1, but if we deliver that level of sweat chloride, we will be confident in the later stage studies that we can drive FEV1.
An important sort of barometer is that ALYFTREK, as an example, in the similar patient population, in homozygous patient population, they delivered a three millimoles of sweat chloride improvement with non-inferiority on FEV1. We're not looking to just beat ALYFTREK. We wanna set the bar high as it relates to clinically meaningful, which is why we set the 10 millimoles of sweat chloride, which again we think will translate to FEV1. But you also wanna speak to the history of what why that's also an important barometer?
Yeah, so first of all, that has been sort of the increment that, you know, the community has looked to. And when you look back at effective modulators or positive trials, you know, where FEV1 has improved when CFTR function has improved, typically those have been when the levels of sweat chloride change and CFTR function change have been 10 or greater. When the levels of sweat chloride change have been in the single digits, sometimes those have translated into FEV1, but just as often they haven't. So we consider that sort of a noisy, risky zone. So for a lot of reasons, we were shooting for being outside of that zone.
Yeah. No, I mean, we would agree with 10 because that's the feedback we get even from physicians. And I think what is remarkable is that ALYFTREK, which doesn't get to 10 even in overall patient population, still seeing a massive conversion, right? Massive uptake. So actually, I'm gonna come back to the patient population because I think there is some confusion that ALYFTREK showed eight millimole, not 2.8. So can you just clarify for that? Because I understand there those are two different studies, different patient populations. So in your patient population of homozygous in PreciSION, what exactly did ALYFTREK did and why eight is not the right one?
Yeah, so you do have to look at the actual genotype of the patient studied. And, you know, obviously their, you know, the treatment effects can be different depending on the genotypes. And so in the F508del homozygous patients, that Alyftrek phase III study did show a 3 millimole per liter change, you know, versus TRIKAFTA in that specific population. It was the compound heterozygous patients, the FMF patients, that in the other phase III Alyftrek study that had a difference of 8 millimole per liter.
I see. So the true comparator, as you're saying, Yatin, is we're in homozygous in the PreciSION CF, which we're targeting 10 or more. The same patient population in ALYFTREK was the 2.8 or 3.
Yes, like the 103 study, right? That's the study we should. Okay. So this is a longer study. It's like three-four months study, right? I understand the treatment durations are long. So just like trying to understand what will be the announcement from would you announce when you have completed enrollment? When should we expect data?
Yeah, so what we've said on both the PreciSION CF study and the healthy volunteer dual combination study that the timing is mid-2026. And, and people do ask us often, can you tighten up that range? What does mid-2026 mean? Specifically on the PreciSION CF, we should be in a better position to provide a little bit more specificity on that timing when we fully enroll, to your to your comment, Yatin. And we once we have enrolled that last patient, it's a little bit easier to forward project how long does it take them to get through the study for us to lock and clean the database, etc. So that would be the plan, is that we would announce when last patient has been enrolled, and then we'll try to tighten up that guidance of what mid-2026 means at that point.
So for sure on the PreciSION CF, with the dual combination work, you know, we're moving through various cohorts and testing different dose ranges. A little bit harder to nail down when we could provide a little more specificity, but as we get more information, we will absolutely try to do that. But as best we can target today, mid-2026 for both of them around the same time. But we're gonna play this out as we get more data. We'll be able to titrate and really give more specificity around the timing of both of those studies.
Got it. Once it is fully enrolled, there is still three-four months, right?
Correct. So we can project from there, right? Exactly. Getting through the study, how long does it take to lock and clean the database, etc. So we can forward project from there.
Okay. So one I mean, I know the commercial strategy is obviously on the dual combo. We'll see what happens if you wanna go into this add-on. But what about ALYFTREK? Would you ever study on top of ALYFTREK?
Yeah, so if we go forward with the add-on, I'll let Charlotte explain this. But yes, that's one of the things you're referencing. One of the strategic decisions we will have to make is when we get that data in mid-2026 with the PreciSION CF study, one of the questions we get a lot now is, would you progress that add-on in addition to the dual combination path that you're pursuing? And we know that both of those paths are commercially viable. We think that ultimately that dual combination could be the best profile for patients because it's a dual combination that has the potential to add clinically meaningful benefit, potentially a different tolerability profile. But that add-on could be very meaningful if we hit that 10 millimole of sweat chloride bar that we've set commercially.
But what we wanna do is see that data and then really assess, can we raise the level of capital to pursue both paths? Can we progress both the dual combination and the add-on? If we progress the add-on, your question is about ALYFTREK, which I'll let Charlotte talk through.
Yes. So again, if we were to progress that, you know, we would absolutely explore, you know, it's really the background standard of care. And mechanistically, you know, the mechanisms of action of both ALYFTREK and TRIKAFTA are the same. And so, you know, that should translate into the, you know, very similar, you know, kinds of paradigms. We chose obviously TRIKAFTA as the background for this proof of concept because it was, you know, has most history. We know it well. And, you know, it made sense for this proof of concept. But yes, we'd absolutely explore that.
Got it. Okay. I think that's all I had on the precision study. On the dual combo study, it's a different NBD1. Why? Like, what is this asset? Why it is different than 719? And, again, you're using two different combos. There are TMD1. Like, just help us understand the strategy there. You want to do one?
Yeah. So I'll start with, you know, first why two different compounds. We took our two NBD1 stabilizers into phase 1 healthy volunteer studies, thinking that we'd pick one. And we had the luxury of, both on the safety tolerability front and on the PK front, being able to choose and being able to deploy both of them in ways that really sort of took advantage of slight differences. You know, one, we chose to take 719 into the add-on scenario because it was a little bit potent, and that really played out at the low doses where we wanted to add that on to TRIKAFTA. And 451 achieved higher exposures.
That actually played out as we think about driving a dual combination where NBD1/451 has to do more of the heavy lifting because it's only two compounds coming together versus four. Both of these compounds actually achieved or exceeded our PK targets. We were able to finesse the properties of the two and take them forward with some kind of, you know, redundancy.
Got it. So in this study, like, what is the goal? Like, so for the previous study, you had those three goals that you highlighted. Like, like, what exactly are we gonna learn here?
Yeah, so it's the dual combination. The dual combination really is two things, right? So it's looking at the combination in terms of the PK profile that we achieve in combination and the safety and tolerability profile of the combinations. And with that data, help us select which compounds we wanna take forward, which dual combination has risen to the top and that we would progress into patient studies from that point. So it's similar to the healthy volunteer studies we did individually that you're looking at safety and tolerability and PK. Now you're just doing it with the combinations. And we always tie back to our CFHBE assay, the exposures that we achieve, to determine where can we achieve what level of efficacy can we achieve in these dual combinations. But it will ultimately help us select that preferred dual combo that we would move forward.
Got it. And the broad sort of middle of this year is still the guidance?
Correct. Still with guidance. Yeah. And we'll refine it soon.
Okay. Any view on the safety profile of TMD1 versus ICL4 if you combine it with an NBD1?
Yeah. So if we look, you know, we chose both of those because mechanistically both of them compare, you know, or, or combine with, NBD1 stabilization to potentially, you know, bring the CFTR protein to, to normal levels. And, and there really was no preclinical or other kind of differentiation. And so, you know, really this phase 1 study will, you know, will really tell us which one, you know, in combination we like the best.
Got it. Maybe question for Elena. Maybe touch on your view of the CF market in general, cash, runway, run rate, and the bond rate.
Yeah. So the market today is about $12 billion. It's expected to grow to $15 billion-$17 billion in the next five years or so. So there's a meaningful opportunity if we deliver on these product profiles we just discussed, we think, to really, provide a lot of value for patients and a big opportunity for Sionna, if we're successful. As far as our cash, we ended 3Q with $325 million in cash, which provides runway into 2028.
Got it. So very good. Thank you. Thank you, everyone.
Yeah, pleasure. Thanks, everyone.
Thank you.
Good to see you all.