All right. Well, thanks everybody for joining us for our next session. My name is David Risinger, and on behalf of Leerink Partners, it's very much my pleasure to welcome members of Sionna's leadership team. Mike Cloonan is here. He's the Company CEO. He's gonna be giving, you know, about a 15-minute or so slide presentation to just set the stage ahead of key events for the company, including data this summer. And also with us, Charlotte McKee to my immediate left, who's the Chief Medical Officer, and Elena Ridloff, the Company CFO. And for those of you who are not in the room, you're missing quite the conference room. Anyway, with that, let me turn it over to Mike.
Thanks, Dave. Good afternoon, everyone. It's a pleasure to be with you today. Appreciate you joining us, and thank you Dave and Leerink for the invitation to do the presentation and the Q&A afterwards. I'm gonna start just with quick background on the company. If you think about what Sionna is doing, many of you may know we're focused on cystic fibrosis, and our goal is to revolutionize the treatment paradigm in CF by leveraging our differentiated NBD1 stabilizers in combinations that have the potential to deliver clinically meaningful benefit to people living with CF. Even though Sionna's only been around for six years, we were formed in late 2019 as a spin-out from Sanofi. The history behind our programs dates back over 15 years ago, where they originated with Genzyme.
We are where we are today in many ways because of that history and the legacy of these programs, but also because of the depths of our experience and expertise in this very important target in NBD1. There are really four key parts to our story, and I'm sure we'll dig into all of these through the Q&A as well. The first is that the unmet need continues to be high in CF. Despite the advancements that have been made, we know the unmet need is high, and you can define that through quality of life expectancy, or the number of people getting to normal CFTR function that have CF. We know today that even for people who are on the standard of care, only one-third of them get to normal CFTR function, so therefore leaving two-thirds not getting to normal.
That's the opportunity that we see with our novel combinations that we'll talk about later in the presentation. If we can deliver new options for patients, new novel opportunities for them to seek treatment in a different manner, in this market today that is $12 billion and growing to $15 billion by the end of the decade, we have a significant commercial opportunity and also an opportunity to create transformational options for patients with CF. The differentiated part of our portfolio is NBD1 . This is not a new target. This is the biology that's been well understood for many years. It's a target that's been studied and had long been considered this holy grail in CFTR function correction, but it's also been considered undruggable for a long period of time.
We know we are the only ones focused on NBD1 today and have that expertise. None of the approved modulators directly stabilize NBD1, so they are truly unique and differentiated. We're also fortunate to leverage the gold standard in vitro CF-HBE assay that you may be aware of. We're very fortunate it's an important tool within CF that allows us to make predictions of the potential clinical efficacy of our programs. We're very confident in our predictive power of our assay. The assay has been validated and has been demonstrated to be clinically predictive. The last part of our four-part program here is that the combination aspect of our strategy. We'll talk a lot about NBD1, but if we want to get patients to fully normal CFTR function, we will do that through combinations.
We have the ability through our own complementary mechanisms to add therapies or compounds to NBD1 that could deliver more patients to fully normal CFTR function. Now let's talk about the NBD1 biology. This is an important part of the story. We know what causes CF. Genetic mutations to the CFTR gene impacts the CFTR protein, and the number one genetic mutation that causes CF is F508del. It affects approximately 90% of patients that have CF. That mutation resides within the NBD1 region of the protein, and the mutation causes NBD1 and the protein to irreversibly unfold at body temperature. It's creating this instability in the protein that's crippling its folding, its trafficking to the cell surface, and then its overall functionality. The standard of care today is a triple combination that is correcting around NBD1.
It's stabilizing and correcting different parts of the protein, so it's partially correcting the protein. It's leaving the thing that most goes wrong unstable, which is NBD1. We know from our CF-HBE assay that if you can correct NBD1, there is no other part of the protein that corrects that level of correction as NBD1 does. If we want to drive patients to fully normal CFTR function, we need to stabilize NBD1 and then combine it with one other corrector that is correcting either ICL4 or TMD1. Through that double combination, which is our strategy, we have the potential to deliver more patients to fully normal CFTR function. From a pipeline perspective, we have two different NBD1 stabilizers that are being advanced based on our positive phase I data, but they're being advanced in two different ways.
SION-719 at the top here you see is our lead program being advanced in our PreciSION CF study that is being tested as an add-on to the standard of care Trikafta. We'll talk more about that study design in a few slides, and I'm sure we'll get into that in the Q&A. Our second NBD1 stabilizer is SION-451, which is the anchor to our dual combination strategy. That is currently in a healthy volunteer dual combination study where we are testing SION-451 with two different complementary mechanisms, SION-2222, which is a TMD1 corrector, and SION-109, which is an ICL4 corrector. The goal of that study is to look at PK and exposure of the combination and the safety and tolerability so that we can make a selection of which combination we will advance going forward.
Both of these datasets, the PreciSION CF study and the healthy volunteer study we expect to have in mid-2026. We've made tremendous progress over the last year, as I've talked about in the completion of the phase I studies for both 719 and 451, the initiation of the PreciSION CF study, and the initiation of the healthy volunteer study with 451. We put ourselves in a very strong position to have a transformational year in 2026 with multiple near-term milestones and catalysts by mid-2026. We're also in a very strong financial position thanks to the IPO we did about a year ago. We now have $310 million in cash at the end of 2025. That gives us cash runway into 2028, well beyond those near-term catalysts that I mentioned before.
Let's set the stage now for both 719 and 451 and what our strategy is and how it was based on the phase I data. If you look at this slide, this is 719 . The left-hand part of the slide is the PK curves of 719 , very encouraging. The right-hand side is the CF-HBE assay, and I'll describe both of them. The key takeaway you're gonna see with 719 , if you look at the PK on the left, before we initiated the phase I studies for both of these programs, we had used the CF-HBE assay to set very specific exposure targets that we needed to achieve to deliver clinically meaningful benefit as either an add-on to the standard of care or as part of our own dual combination.
That target was based on us being able to deliver a 10 millimole sweat chloride improvement above the standard of care, whether that's as an add-on or as part of our own dual combination. With that 10 millimoles of sweat chloride, it would give us confidence that we would also be able to deliver three percentage point improvement in FEV1. If you look at the PK, you see two different teal hash lines. The lower line is the add-on target. If we add 719 on top of Trikafta to deliver that 10 millimole sweat chloride improvement, that's the target. Then the dual combination is higher, same clinical target, but it's a higher exposure target because here, NBD1 is only being combined with one other asset in a dual combination.
In that case, NBD1 needs to do more of the work as part of a dual combination to deliver that exposure and the efficacy we seek. The takeaway from the PK you see here is for SION-719, every dose we tested exceeded the add-on target, and every dose at 40 milligrams or above exceeded the dual combination target. We ultimately selected SION-719 to be the lead as part of that add-on strategy to the standard of care because of its potency at the lower doses. If you look at the right-hand side and the translation back into the CF-HBE assay of the exposure that we achieved in phase I, you can see that black dot on the reference point at the 1.0, that's Trikafta. That is the standard of care today.
This measure, the assay measures chloride transport, so it tells you relative Trikafta, where do we need to be to deliver clinically meaningful benefit above Trikafta. The teal hash line on the right represents the lower teal line on the PK curve. That's the add-on target above Trikafta to deliver that 10 millimoles of sweat chloride. If you look at the maroon-shaded rectangle there, that is us plotting the PK or exposure that we achieved in the phase I at lower doses on top of Trikafta. That's the range of possibilities. We are above the minimum hurdle of 10 millimoles of sweat chloride all the way up into wild-type levels of CFTR function. Similarly, this is 451, a similar PK plot on the left-hand side, the CF-HBE assay. The takeaways you'll see here for 451 is similar to 719.
At all doses we tested, we were above the add-on target, and at every dose from 75 and above, we were above the dual combination target. We ultimately prioritized 451 as the anchor to our dual combination target because of the exposure we were able to achieve at the higher doses. It was a better profile for the dual combination option than 719. Similarly, you can see here on the right-hand side the mapping of the CF-HBE. You can see the comparison to where Trikafta sits at the 1.0. The minimum target is the teal hash line of 10 millimoles of sweat chloride, and that maroon-shaded rectangle shows the exposures at the higher doses of 451 plotted back into the hBE, showing us we have the potential to be above the 10 millimole bar and potentially even into wild type.
Very encouraged by both the opportunity of 719 and 451 to deliver these profiles, both worthy of being advanced. From a strategy, a clinical strategy, you can see we have our two-pronged approach where we've got 719 being moved forward as the add-on to Trikafta proof of concept study, the PreciSION CF study. That study is enrolling now CF patients. We expect to have the data in mid-2026. Similarly, you can see the path of 451 as the anchor to our dual combination strategy being combined with both 2222 and 109. We expect to have that data by mid-2026 as well.
As a reminder, the healthy volunteer study will give us safety and tolerability and exposure and PK profile of the combination that will ultimately help us select which of the dual combinations we would progress forward into CF patients. Our strategic decisions on data in mid-2026 is gonna be selecting the preferred dual combination we'll move forward, and then we also have a decision to make whether we would continue to advance the add-on strategy beyond the proof of concept. We know that both of those paths are commercially viable and attractive if we can achieve that 10 millimole sweat chloride bar that we have set. With the add-on, we haven't committed yet to advancing that because we wanna first see the data, and then we wanna make sure the capital is available for us to progress both paths.
The dual combination is our prioritized path, so we wanna make sure we have the capital to continue to pursue that path. If the data is positive on the add-on and the capital is available, that would be something we'd be open to discussing at that time. Let me just talk real quick about the trial design. We'll get more into this with Charlotte here today, but we're very excited about this PreciSION CF study. It's the first time we're testing an NBD1 stabilizer in CF patients. It's a very efficient study that is a two-way crossover. Its design is to have a 10 millimole sweat chloride. It's powered to have a 10 millimole sweat chloride improvement above the standard of care. What you can see here is a two-way crossover. Everyone comes in on their physician-prescribed Trikafta.
They never have to come off their Trikafta, and they will have two different periods of time where they're either on 719 plus Trikafta or they're on placebo and Trikafta. Each patient becomes their own active control, so very efficient and powerful study. The goals of this study, I talked about the sweat chloride. The first thing we wanna show here is the ability to improve CFTR function by adding 719 on top of Trikafta, deliver that 10 millimoles of sweat chloride. If we can do that in this study, it will give us confidence in later stage studies that we will see that improvement in FEV1 as well. The second part, and the key part of this study that's important for us, is it's gonna demonstrate that NBD1 is mechanistically different from, and yet synergistic with the components of Trikafta.
It's a very important study for us to demonstrate the NBD1 biology. Then third, this will be the first opportunity for us to show the translation of the CF-HBE assay in CF patients with an NBD1 stabilizer, a very important opportunity for us to prove out and demonstrate that translation. It will also be used as we think about even the dual combination and leveraging the learnings from this study on the assay. Very important part of this study, setting expectations at that 10 millimoles and all of the other benefits we get from the study. From a commercial and unmet need perspective, just a couple of points to highlight here. Many of you may know CF is a large rare disease with over 100,000 patients today.
As I mentioned before, 90% of them have F508del, a form of the F508del mutation. The unmet need continues to be high. We focus a significant amount of attention on the number of patients who are not achieving normal CFTR function. That's two-thirds of patients who are on the standard of care today are not achieving normal CFTR function. That's an opportunity for us with our NBD1 combinations. Lastly, as we said, if we can deliver these new options for patients that have meaningfully differentiated efficacy, there is an opportunity to not only create something transformational for patients, but it's a significant commercial opportunity in this $12 billion market today that's growing to $15 billion-plus in the future.
To wrap up, and then we'll turn it over to the Q&A, we are at a very strong position today as Sionna. We are in a unique position to potentially positively disrupt the CF space because of our NBD1 stabilizers and the combination strategy. The unmet need continues to be high, as we've talked about. We are well-positioned both scientifically with our clinical expertise and from a capital perspective to pursue the strategy we've outlined, which is 719 as the add-on, 451 in a dual combination. We have near-term catalysts on the horizon in mid 2026, and as I said, the capital to pursue that into 2028. Looking forward to this coming year. The team is doing an outstanding job.
We're gonna continue to execute, and we look forward to turning those cards over in the near term. With that, I'll stop here, and we'll turn it over to Dave.
Excellent. Thanks very much. That was a great presentation. I wanted to go back to basics a little bit and just go back to the development of SION-719 to start. It'd be helpful to just understand why this target has been so difficult for drug developers historically and how Sionna and its really its predecessor entities cracked the code.
Yeah, I can start and then Charlotte can weigh in on this as well. Dave, it really goes back to the history of the science behind NBD1. It's been studied by companies like Pfizer. We know Vertex has tried at various times to crack NBD1. It is a challenging target. The medicinal chemistry is a very challenging exercise because of the very shallow binding pockets that exist around NBD1. When you think about the history that I mentioned early on in the presentation, right? The science behind our programs goes all the way back to Genzyme over 15 years ago. It continued through Sanofi. We wouldn't be where we are, having been able to crack this tough target without that perseverance, the level of investment that was made.
I would really say where it turned, right? Where there was that breakthrough that Sanofi finally had, and it was really when Sanofi changed their approach from traditional means of trying to find hits from high-throughput screening to more of a structural biology-based approach. Leveraging X-ray crystallography, really understanding where and how these compounds bound. Also leveraging the hBE assay to determine the efficacy and the potential of these compounds. Then they started to build them up atom by atom to get to these highly potent stabilizers that we have today. It was really a decade-plus of perseverance, effort, leveraging the learnings and trying a different path when you saw the ones that were shut off from high-throughput screening weren't working, having the courage to shift that.
When we spun out in late 2019, these were still early-stage compounds. We were able to then have a very dedicated CF-only company that put all of our efforts into advancing these compounds. We weren't fighting over resources of different programs or different therapeutic areas, we were hyper-focused, and our core was CF. We were able to take these early-stage compounds and now progress them into the clinic with very promising data and near-term catalysts on the horizon.
Excellent. Could you just talk about sort of how we should think about the safety profile to date for SION-719, and also the potential for drug-drug interactions, because that's obviously critically important with this category of medicines as well?
Yeah. Maybe I'll start out, you know, we know from, you know, we've shown the single agent 719 and 451, phase I healthy volunteer data in those single agent studies. The safety and tolerability profile was very favorable, and that was actually what gave us the umbrella together with the exposure that Mike showed you to consider advancing both of those compounds into, you know, the differentiated path that we had. We know from a safety perspective, there's nothing that has been described as on target, you know, in terms of safety findings across the modulators. CFTR as a target, you know, doesn't necessarily have safety call-outs or, you know, things to be of specific concern.
We are just being, you know, I think, very diligent and looking the same way you would develop any small molecules, looking across the safety profile and really looking, you know, just to be vigilant drug developers, you know, as we look. There's no specific either CFTR or NBD1 call-outs, you know.
Excellent
on the safety side.
Excellent. Sorry, did you have more to add?
I know there was a second part of that.
DDI.
Yeah, the DDI. You're absolutely right. You know, when we started and as we advanced into the 719 add-on to standard of care profile, you know, we had to be cognizant of the landscape and the standard of care profile. We did, you know, as we predicted from our in vitro data, we did adjudicate any potential DDIs, you know, that would be important, you know, as we advanced 719 on top of the standard of care. In our dual combination, we specifically selected the complementary modulators that had differentiated metabolic profiles because, you know, we want. One of the things that we're looking at is how these two combine, you know, in our dual combination.
All, you're right, very important and things that we're looking closely and carefully at.
Got it. Just with respect to the phase II trial, it's obviously extremely small, so why 16 and why not 20 patients?
Yeah. Yeah. You know, in any study, you just have to, you know, you have to brutally prioritize, right? You know, what we wanted. You know, we're not. You can't answer every single question with every single study. For us, it was important to show really proof of biology, proof of concept in as efficient a way as possible. Frankly, we could leverage the endpoint of sweat chloride to really do that very efficiently. You know, more patients are always interesting, but with the two-way crossover, knowing the variability of sweat chloride and the characteristics of it as a really clinically very predictive biomarker, we are well-powered for that 10 millimole per liter change in sweat chloride with well under 20 patients. We didn't need more, you know? We really.
You know, that's where we put the line in the sand.
Excellent. Very helpful. Maybe you could just add a little bit more on the design of that trial, the entry criteria, how we should think about, you know, what percentage of Trikafta patients on therapy today are in the range of sweat chloride that you're looking at, et cetera.
The goal, the population we're interested in, we're looking for this particular study was, you know, patients who are on Trikafta as a, as a proxy for any standard of care who had what we would consider kind of a typical Trikafta response. This is gonna be based on sweat chloride. We're not, you know, we're not describing exactly what those numbers are, but you can say, you know, think conceptually of the range of patients who have had a typical response but yet retain a dynamic range because our endpoint, our primary activity endpoint is sweat chloride. We wouldn't, for example, want to enroll patients on Trikafta who are already in the normal range.
We've tried to maintain a dynamic range but still enroll patients who, based on what we know from the epidemiology and real world, you know, have had a pretty typical response. As if we were to take that program forward into later stages, we would certainly consider broadening the criteria. For this, really, you know, because it is such an efficient small study, you know, we're really optimizing what we consider kind of a sweet spot in terms of CFTR function.
Got it. What will the read-through be to 451 from that data this summer, assuming it hits your target product profile?
Great. Yeah. I'll start. We, you know, have made predictions for the SION-719 add-on study based on our CF-HBE assay. As we've said, this, you know, this PreciSION CF study will be the very first line in the sand where we clearly correlate back to those CF-HBE assay predictions with SION-719. It's the same assay that we're using to make predictions about the dual combination or any other combinations. That, you know, that biology, you know, when we, as we expect, you know, if we predict and respect and expect to prove that biology, that is gonna read through to the same assay that is, you know, predicting our dual combination.
Yeah. I would just one thing I'd add, David, Charlotte sort of referenced this, is that this is a proof, an NBD1 proof of concept. We just happened to take 719 as the asset to move into this study, but the reality, this is an NBD1 proof of biology. If we demonstrate with 719 all of the things that we've said about mechanistically 719 being different than the components of Trikafta and yet synergistic, we drive CFTR function improvement, and we see the translation in the assay. All of those things help the dual combination strategy and further validation of that. Because as Charlotte said, the assay, it's the same model we're using. We would just put in different assumptions. The add-on on top of Trikafta is a set of assumptions in that model.
The 451 dual combination strategy is a different set of assumptions, but in the same tool.
Got it. Could you just provide a little bit more color on how the two drugs differ, right? Just be helpful to understand, you know, the nuances between the two so that we can think about that translation, that read-through.
Yeah. Both of them, 719 and 451 are from what we call our second generation, highly potent NBD1 stabilizers. They're, you know, related chemically. 719, as you've heard us say, 719 is a little more potent than 451. They both, we know, you know, they're hitting the same target. They're, you know, probably more similar from a very high level than they are different.
They have some characteristics, particularly that potency, that really, when we had the luxury of being able to consider working with both of them and taking potentially both of them forward, the potency of 719 played out really, especially in those lower dose ranges that we were interested in when, as, you know, for all sorts of reasons, when we would be combining the NBD1 stabilizer with the standard of care. We don't need very high doses, and there are good reasons not to, you know, use very, very high doses. 719 really played particularly well in that zone.
SION-451, we achieved higher exposures, and that, in the dual combination, that was where that really became an advantage for potentially really moving the possible efficacy bar higher, in dual combination.
Excellent. Could you just talk a little bit about the, you know, for the combination data sets that are coming, how many pills are being administered, you know, and then what the go forward might be if you choose, you know, either one?
Yeah. We're far away from, you know, pill counts and things like that. You know, we're really in the zone of optimizing and really looking deeply at safety tolerability and PK. As we think about taking those programs forward, we'd obviously be looking at, you know, pill burden and other sorts of things in later stages. We hope to be answering those questions and thinking deeply about that in the later stages.
Got it.
Yeah. I wanna
Once we-
Oh, go ahead, sure. Go, Elena.
Once we select a dual combination, then we can start to work on things like co-formulation and other things that would be optimized for a launch.
Makes sense. I think it's notable that, you know, the vision and the clear strategy is to move forward without a potentiator. I thought it would be really helpful for you to characterize that in a little bit more detail.
Yeah. That's interesting. You know, when we look at our preclinical data, and we really leverage the deep biology and, you know, our preclinical assays across a number of different domains and types of assays. With NBD1 stabilization, we don't see the need for a potentiator. Now, a potentiator, you know, you probably know this, we do have actually a potentiator in our pipeline that we in-licensed from AbbVie. A potentiator can always be helpful in any scenario, possibly as, like, a boost, you know, potentially. We think of it as more, a potential tool for life cycle development.
What we see from the biology is we don't see a need when you stabilize F508del CFTR with NBD1, we don't see a need, a dependence on a potentiator. It gives us some flexibility there.
Very interesting. Excellent. Mike, I think you mentioned, you know, the cash runway, but Elena, could you just talk a little bit about cash position and sort of, you know, taking us from, you know, that point forward?
Yeah. We ended 2025 with $310 million in cash, which gives us cash runway into 2028, so meaningfully past the midyear milestones Mike and Charlotte spoke to today. We're in a strong cash position.
Also maybe talk about, I mentioned the strategy of do we go forward with the add-on or not. Maybe talk a little bit how we think about that capital decision as well.
Yeah.
Great
We've assumed currently in our cash runway that we prioritize the dual combination after these readouts midyear. As Mike alluded to, both the add-on and the dual combination are commercially attractive opportunities, and there could be an opportunity to even co-position those. Once we have the data sets, assuming the data supports it, there is the potential opportunity to also advance the add-on, but that really will be more of a capital allocation and capital-driven decision versus strategic decision because we do know these are both commercially attractive opportunities.
Excellent. Well, we are over time. This has been great. Thank you so much for being with us.
Thank you, Dave. Appreciate it.
Appreciate it.
Thanks, Dave.
Thank you.