Good morning, everybody. Thank you so much for joining us here on Day 2 of the J.P. Morgan Healthcare Conference. My name is Bhavana Balakrishnan . I am an associate with the Healthcare Investment Banking team. Thank you for joining us here for the presentation of Sionna Therapeutics. With us, we have Mike Cloonan, President and Chief Executive Officer, Elena Ridloff, Chief Financial Officer, and Charlotte McKee, Chief Medical Officer. Over to you, Mike.
Thank you so much. Great to see everybody. Thank you all for attending today. It's a pleasure to be with you, and thank you, J.P. Morgan, for the opportunity to present. These are our disclosures. We will make forward-looking statements today. Actual results may differ from those statements. Sionna, as you may know, is on a mission to revolutionize the treatment paradigm in CF by leveraging our first-in-class NBD1 stabilizers in combinations that have the potential to drive clinically meaningful benefit above the standard of care. We have a rich history. Even though we were only formed as a company in late 2019, we were a spinout from Sanofi at that time. But the science behind our programs originated at Genzyme over 15 years ago.
That's an important part of the story because we wouldn't be where we are today going after this very challenging target in NBD1 without the level of perseverance and investment that was made between Genzyme and Sanofi. We are really well-positioned at this point to positively disrupt the CF market with a new mechanism of action in NBD1 and the combination strategy that we are pursuing. There really are four key parts of the Sionna story that we'll touch on in the presentation, and I'll start here with a summary. The first is the unmet need. Despite the advancements that have been made in CF over the last several years, the unmet need continues to be high in CF. You can define that through multiple ways.
You can look at it from a quality-of-life perspective, a life expectancy, or what we often talk about, getting patients to normal CFTR protein function. And we know today that for patients who are on the standard of care, only one-third of those patients get to normal CFTR function. So that leaves two-thirds having an opportunity to achieve higher levels of CFTR function. We believe we have an opportunity to do that with our novel mechanism in NBD1. And if we can do that, if we can deliver meaningful new options for patients that potentially raise the efficacy bar, not only would that be an amazing opportunity for patients to have more options, it's a significant commercial opportunity. The CF market today is a $12 billion monopoly, and it's growing to $15 billion plus by the end of 2030.
The core of what you'll hear us talk a lot about is NBD1, this target. It is not a new target. It's not a new mechanism. It has been well-understood and well-studied in the past. The biology behind NBD1 is very clear in this space, but it has long been considered this undruggable target, the holy grail in CFTR correction. We are here today with multiple clinical assets on NBD1 and about to refute that undruggable label that has existed for many, many years. NBD1 really is the key to fully correcting the protein, as we'll talk about later in the presentation. We also know that none of the approved modulators directly stabilize NBD1, so it is truly novel, differentiated, and first-in-class. We are also fortunate to leverage the gold standard in vitro CFHBE assay, which has been demonstrated to be highly predictive of clinical outcomes.
We have a lot of confidence in our CFHBE assay and what it tells us is possible with our combinations. And when we look at our multiple runs of our CFHBE assay with NBD1 in combination, it shows us that we have the potential to raise the efficacy bar in CF through combination therapy. And then that speaks to the last part here, the fourth item. As much as NBD1 is a critical part and the differentiated part of our portfolio, we are also investing in complementary mechanisms that, when you combine them with NBD1, this is where we have the potential to deliver wild-type levels of CFTR function fully normal. Let's talk a little bit about the biology of NBD1. Why is it so important, and why is it so critical in what we're doing? We know what causes CF.
It's genetic mutations to the CFTR gene that impact the CFTR protein. The number one genetic mutation that causes CF is F508del. Approximately 90% of patients have a form of that mutation, and if you look at the graphic here, you can see F508del, that mutation resides within the NBD1 region of the protein, and what that mutation does is it causes NBD1 to irreversibly unfold at body temperature, so it is creating this instability not only in NBD1, but in the protein, crippling its folding, its ability to traffic to the cell surface, and then the overall functionality. The standard of care, as you may know, Trikafta, is a triple combination, and it is correcting different parts of the protein, not directly stabilizing NBD1. It is correcting around NBD1 by correcting ICL4, TMD1, and TMD2. Therefore, it's partially correcting the protein, and NBD1 is still unstable.
So we see this as a very novel opportunity for us, as I said, to potentially disrupt the CF market. And when we look at all of our preclinical data that we have on NBD1, when we stabilize and correct NBD1, it does something fundamentally different than the approved modulators to that protein. And one specific example of that is in our CFHBE assay. When we model the monotherapy, the single agent of NBD1, and we compare the level of correction to Trikafta, a triple combination, that efficacy is nearly equivalent, the single agent nearly equivalent to the triple combination. So that speaks to the power of NBD1 and what it can do on its own. Our goal is to get as many patients to normal CFTR function.
The way we do that is stabilize NBD1 and then correct just one other part of the protein to form a dual combination that has the potential to drive more patients to fully normal CFTR function. Let's talk about the pipeline. We have a deep pipeline, both in terms of our NBD1 programs and the complementary mechanisms that I referred to before. Both our SION-719 and SION-451 NBD1 stabilizers have positive phase I data, and they are both advancing to the next stage of development, but in two different ways. SION-719 at the top that you can see here is advanced into a phase IIA proof-of-concept study in CF patients called our Precision CF Study.
And we'll talk about that study and design in a little bit, but we're expecting to have the first patient data from an NBD1 compound, 719, on top of the standard of care by mid-2026, and we are on track to deliver that data. We also have 451, another NBD1 stabilizer that we are using as the anchor to our dual combination strategy that I described before. 451 is in a healthy volunteer dual combination study where we are combining 451 with one of our complementary mechanisms, 2222, which is a TMD1 corrector, and we are also combining 451 with SION-109, our ICL4 corrector. That data we also expect to have in the middle of 2026. This past year, 2025, we made meaningful progress across our portfolio in advancing the company.
I spoke about the two NBD1 programs, SION-719 and SION-451, both completing their phase I, having positive data. They've both advanced to their next stage of development. SION-719 is now in the ongoing Precision CF Study, our phase IIA proof-of-concept study, and SION-451 is the anchor to that dual combination healthy volunteer study that I mentioned before. We also completed our IPO earlier in the year, which has positioned us nicely from a capital perspective to have cash runway into 2028, well beyond those catalysts and milestones that I referred to in mid-26. So let's talk about our two lead stabilizers for NBD1 and the phase I data that we've presented in the past. If you look at the chart here, I'm going to first focus on the PK on the left and then the HBE curve on the right-hand side.
So this is 719, one of our first stabilizers that has completed the phase I data. You can see on the left the PK curves. We tested multiple doses of 719. The PK exposure is on the y-axis. It's a log scale. And what I really want to point out, if you look at these two teal hatched lines, one that says the add-on target and the higher one says the dual combination target, we leveraged our CFHBE assay to set very specific exposure targets ahead of the phase I data. That assay helped us imply what the exposure is needed to deliver in order to hit clinically meaningful benefit above the standard of care.
As an example, that add-on target, the lower target, represents a 10 mmol sweat chloride improvement over the standard of care, which we think will equate to a 3 percentage point improvement in FEV1 as well. That is the bar for clinically meaningful, and that's the target we set as one option to combine 719 as an add-on. The higher target is the dual combination strategy that I referenced before. It's a higher concentration target because this is just two drugs coming together. NBD1 has to do more of the work in that scenario, but the clinically meaningful target is the same: 10 mmol of sweat chloride, 3 percentage point improvement in FEV1. The takeaway from the 719 PK study is that at every dose we tested, we exceeded that add-on target on top of the standard of care.
For every dose from 40 or above, we were above the dual combination target. We have selected 719 to advance as our add-on to the standard of care compound because of its potency specifically at lower doses. Now, when we look at the right-hand side, this is our CFHBE assay, that gold standard in vitro assay I mentioned before. We have now plotted the PK exposure that we've achieved in that phase I with 719 into our HBE assay. A couple of things to point out. The assay measures chloride transport, and we have put the y-axis into a relative scale so that you can compare us to the standard of care. So if you look at the 1.0 reference point, that is Trikafta, elexacaftor, tezacaftor, ivacaftor at the 1.0.
You can see that same teal hash line that I mentioned before that denotes clinically meaningful benefit, 10 mmol of sweat chloride when we add 719 on top of Trikafta, and now, if you look at that maroon-shaded rectangle, this shows you the range of efficacy possibility that we have with 719 when we add it to Trikafta at our lower doses, and what this tells you is we have confidence we're above that minimum bar to deliver clinically meaningful benefit all the way up potentially into wild-type levels of CFTR function, normal CFTR function. Now, similarly, this is 451, our second NBD1 stabilizer. Similar plots, the PK on the left, the HB on the right. What you'll see here is the same hash lines that I mentioned before representing that clinically meaningful bar that we set ahead of the phase I studies.
And with 451, at every dose we tested, we exceeded that add-on bar, and at every dose from 75 milligrams and above, we exceeded the dual combination bar. We selected 451 as the anchor to our dual combination because of how high the exposure we were able to achieve with 451. And in the dual combination, that's what's important: driving more exposure, the ability to drive higher levels of efficacy in a dual combination, and it's an excellent opportunity for us to progress both 719 and 451, leveraging their unique differences. Similarly, on the CFHBE, it's the same relative scale comparing to the standard of care Trikafta. You see that hash line representing the clinically meaningful bar and that same maroon-shaded area. This is now the dual combination where we're combining 451 with just one other compound at the higher exposures.
You can see here we're above the bar for clinically meaningful benefit all the way up potentially into wild-type levels of CFTR function. So very pleased to have that positive data for both 719 and 451. Now let's look at the clinical strategy and our portfolio strategy and what comes next. So 719, as we mentioned, is going to advance as the add-on on top of Trikafta. It has already initiated that phase IIA proof-of-concept study, the Precision CF study that I mentioned before, and I'm pleased to say we are on track to deliver that data in mid-2026. We're very happy with the execution of the trial and the sites, and we look forward to sharing that data in mid-2026.
And on the bottom, you see we have a parallel path for the dual combination where we're combining 451 with both 2222, one of our complementary mechanisms, and also 109, one of our other complementary mechanisms. The goal of that study is to generate PK in combination of those two different dual combos and also assess the safety and tolerability profile of both combinations that we will ultimately select the best dual combination to progress from there to advance into a phase IIA dose-ranging study in CF patients. We also expect to have that dual combination data, the healthy volunteer data, in mid-2026, so an important time for us to have both data sets. Strategically, just so everybody understands what we're doing here, our first priority in terms of advancements is the dual combination path.
We think ultimately that has the best profile both for patients, something that you could drive to higher levels of efficacy with just two compounds, potentially even a different tolerability profile. We think it has a real benefit to patients. The add-on to the standard of care, at this point, what we have said is if that data is positive, we will have an opportunity to assess whether we would progress both paths forward. Will we continue to progress the add-on and the dual combination? We know both of these paths are commercially viable and can be co-positioned that they can work together in the marketplace with multiple options for patients, but what we want to make sure is that we have the capital to progress both of those pathways.
So when we have the data, we'll assess that data and we'll make that decision on the add-on whether to progress that as well as the dual combination. Now, just a quick background on the Precision CF. This is an elegant, efficient study design for the proof-of-concept of 719 on top of Trikafta. As you can see, this is a 2A crossover study where each patient will act as its own control, and we need less than 20 patients to power this study to a sweat chloride improvement of at least 10 mmol. So you'll continue to hear that number from us. 10 mmol of sweat chloride is the minimum threshold that we have set for clinically meaningful, which we also expect in later stage studies to demonstrate FEV1 improvement. This study is a sweat chloride test or sweat chloride study.
It's not meant to show FEV1, but we fully expect if we deliver that level of sweat chloride improvement, we will see FEV1 in later stage studies. So when we fast forward to mid-2026, and what does success look like for Sionna specifically on the Precision CF study? The first is that 10 mmol sweat chloride bar. If we achieve that, we know we have hit the clinically meaningful bar that would make a meaningful impact for patients in CF. And so that's the first definition of success. We know that that bar is the right bar to achieve for two reasons. The historical benchmarks in CF have demonstrated a 10 mmol sweat chloride improvement that also has the potential to equate to three percentage points or more of FEV1, is clinically meaningful. We've also engaged with the community to understand from them, has anything changed?
What would be clinically meaningful in your mind to get excited about a new option in CF? And it is very, very consistent. And it's also important to note that Alyftrek, the new triple from Vertex, in the same homozygous patient population where we are projecting a 10 mmol sweat chloride improvement, Alyftrek delivered three mmol of sweat chloride improvement. So that's the relative comparator to think about. If this study is successful and we've delivered that 10 mmol, as we said, we will make the strategic decision as to whether to continue to advance that program forward. But what it will do for us is it will demonstrate in this study that NBD1 is mechanistically different from and yet synergistic with the components of Trikafta. The first time we'll be able to demonstrate NBD1 in CF patients.
It's also the first chance that we have to validate our CFHBE assay in CF patients, a very important milestone that will help us build additional confidence in our CFHBE model, which will then translate to the dual combination strategy as well. So a very important study on the horizon for mid-2026. Let me just quickly touch base. I mentioned the unmet need and this commercial opportunity. It's worth showing this graphic, which is a post-marketing CHEC-SC study that is showing sweat chloride levels for patients on approved modulators. If you look to the far right, this is patients who are on Trikafta. The black dots all represent an individual patient and their sweat chloride level. What is important to see here is, yes, you see significant improvement when patients go on Trikafta, which is a great benefit to the patients.
But what you also see is you see where the normal line starts, where normal sweat chloride is, which is 30 mmol or less. Only a third of patients on Trikafta achieve that normal level of CFTR function. You can see all the patients above normal. This is important to us as we think about trial design, patients that will enroll. We want to deliver more of those two-thirds of patients that are not fully normal to get to that level of sweat chloride. And then when we think about the commercial opportunity, this is a large, rare disease that's well established. Over 100,000 patients worldwide. Our target population, as we've talked about, is the 90% of patients who have the F508del mutation. You've seen the unmet need that exists for patients not getting to normal. We know that more options for patients are needed.
If we can deliver that in this $12 billion market that is growing, we could potentially add meaningful benefits to patients and drive significant commercial uptake for Sionna. In closing, Sionna is well positioned to positively disrupt the CF space. We have first-in-class NBD1 stabilizers that in combination show the potential to deliver clinically meaningful benefit above the standard of care. We are well positioned. We have an excellent team. We have novel and distinct science, and we have the capital to pursue our strategy, and we have near-term catalysts on the horizon. We're very much excited for the coming year and the continued execution to set up these milestones going forward. With that, I'll stop, and we'll open it up for Q&A.
Thank you, Mark.
Okay.
Here's a bit of a personal question, but have you ever considered going after Hets with 508, though?
Yes, we will. I'll let Charlotte describe the plan. The initial study is just homozygous. The broader plan will include Hets, but I'll let Charlotte talk about that.
I think targeting NBD1 stabilization and Hets, and I happen to be one and my family members are, makes a lot of sense because it's actually not a silent phenotype.
Yeah. Go ahead, Charlotte.
Yes. Our target population is basically anyone with at least one F508del, and that is certainly the majority of those patients are homozygous as a group, but absolutely that is part of our long-term strategy.
I have a question. As you think about your dual prioritization strategy, how would you compare the commercial opportunity for the 719 add-on versus the 451 dual combo?
Yeah. Elena, you want to take that?
Sure. So as Mike was articulating, we think there's attractive commercial opportunities for both of these profiles. So today, this is a $12 billion market expected to grow. If we can deliver what we expect as far as improving efficacy, both either with an add-on or with a dual, there's a tremendous population, two-thirds of patients who are not today at normal. And as we've done preliminary market research, what we hear is that there's a ton of enthusiasm for a novel dual combination. Today, Trikafta and Alyftrek are three drugs. Adding 719 would be four. So to have two drugs that could potentially have a superior efficacy profile and potentially a differentiated safety profile, there's a lot of enthusiasm for that. As well, there's enthusiasm for patients who today are well tolerated. There are patients who are happy with their current standard of care but would like more efficacy.
We do think there's an opportunity where these could be either individually very successful commercial launches and also potentially co-positioned if we were to decide to pursue both and have a very nice commercial opportunity for either or both in the market.
As you think about prioritization within the novel combo itself, how would you think about your ICL4 versus your TMD1, and what sort of data do you need to see to be able to come to that decision?
Go ahead, Charlotte.
Yeah. I'd say mechanistically, when we look at our CFHBE assay, either of those TMD1 or ICL4 modulators, they're both interface domain modulators. So either of those actually has the potential to fully correct CFTR function when combined with an NBD1 stabilizer. So mechanistically, we're really agnostic. So it really will be the PK and safety profile that really we see as we call this phase I healthy volunteer study our sandbox. So it'll be really the components and their individual properties in combination with NBD1 stabilization.
When you think about the data that both physicians as well as community need to see, what do you think is required and what is the bar to incentivize and sort of give comfort for the community to switch from SOC?
Yeah, I'll start, and then Charlotte, she has a lot of history in CF. When we think about what we think the regulatory bar will continue to be in CF is FEV1. We think that's the primary endpoint. Then in our later stage studies, as we move into dose ranging in the phase III, that will continue to be the bar. Sweat chloride is a very important secondary marker, and the road to FEV1 improvement tends to lead through sweat chloride, which is why we're starting there. We continue to believe if we want to show clinically meaningful benefit beyond the standard of care, it will be FEV1 will be the determinant of that. We think that will drive the switching, the adoption, because it is the marker that people look at specifically around efficacy in CF. I don't think you'd add, Charlotte?
No, I would just reinforce we do expect in our driving, just to reinforce too, an improvement in FEV1. We see that possibility, but then it's the benefit-risk profile on an individual patient basis.
What can you learn from recent launches in the space, both in terms of bar for success as well as you think about launch in a few years? What are main learnings for you?
Yeah. I mean, I'd say that the most recent launch is Alyftrek, and I think it's still early days for Alyftrek to see what it will do. But when we look at the profile of Alyftrek relative to Trikafta, which is the standard of care, what we see from the phase III data is that Alyftrek was not inferior on FEV1. So there was no improvement in FEV1 from Alyftrek versus Trikafta. They saw a slight increase in sweat chloride in the homozygous patient population. It was 3 mmol improvement in sweat chloride. In the heterozygous patients, it was an 8 mmol improvement. So for us, we're setting the bar higher than that.
We want to hit that 10 mmol or more because we believe if you look at the history of the modulators that have been approved, when you're in that single-digit improvement in sweat chloride, sometimes you achieve FEV1 improvement, but just as often you do not, and so we want to be outside the noise as it relates to sweat chloride and deliver that 10 mmol or more, which we then fundamentally will help drive that FEV1, so what I think we're seeing is that without the FEV1 improvement in Alyftrek with the sort of modest improvements in sweat chloride, we haven't seen the full uptake yet, but historically, I would say it's an efficacy-driven market, and when you have the FEV1 and the sweat chloride together is where you have the potential to drive the highest level of adoption and the most benefit for patients.
You spoke in the beginning about the challenge of NBD1 stabilization. You just talk about kind of the journey to where you are today.
Yeah, happy to. It's a great question. It has been a journey. As I mentioned, the history there, it's taken us 15 years between Genzyme, Sanofi, and now Sionna to have programs in the clinic, and so what really the challenge has been about NBD1, the binding pockets around NBD1 are very, very shallow. So it's a very challenging medicinal chemistry exercise to develop compounds that can bind to NBD1, and over the period of time that this was being developed within Genzyme and then Sanofi, there were several learnings that took place to really help them break through, and then Sionna took it to the next level. And a lot of that was a structure-based biology approach to developing these compounds where we really built the compounds up atom by atom, looking at the activity, leveraging the CFHBE assay. We have over 150 X-ray crystal co-structures.
It was a tremendous amount of effort that went into thinking through these compounds and which ones could rise to the top, and ultimately looking at activity in the assay to help us prioritize which compounds we move forward. There is history in that we know there have been other companies that have tried to tackle NBD1. Pfizer is one company that wrote an article about this back in the 2015, 2016 timeframe after they took a long hard run at NBD1. And even though they couldn't say it definitively from their work, their conclusion was this could be an undruggable target, and they specifically referenced the shallow binding pockets, so Pfizer tried. We also know that Vertex has stated publicly they have tried to crack NBD1, and I think the words they used was they couldn't optimize this target.
To their credit, they found other ways to partially correct the protein. It is a challenging target for sure. We're well positioned based on the history and the knowledge that we have. Our IP estate protects us significantly. We continue to innovate and develop new NBD1 compounds even behind what you're seeing with 719 and 451. We want to continue to be a leader as it relates to NBD1 in the future.
How should we think about your runway and which milestones are you fully funded to?
Yeah, so we ended Q3 with $325 million in cash, and we have cash runway into 2028, so that takes us meaningfully past these milestones mid this year.
Any other questions from the audience? Mike, I'd like to turn it over to you in case you had any closing remarks.
I would just say, one, thank you for everybody for attending today, live and in person. It's a pleasure to have the opportunity to present. As we talked about, it's a very meaningful year for Sionna. We have set ourselves up for 2026 to be very impactful with our two programs that we expect to have data in mid 2026. The precision CF study is enrolling nicely. We're excited to share that data when it comes in mid 2026. It'll be the first time we'll be able to share NBD1 data in CF patients. And as I said, it's going to give us multiple opportunities to show the potential to increase CFTR function and to show our assay translation in CF patients. At the same time, we've got this opportunity with our dual combination strategy to select that best dual combination from that healthy volunteer study in mid 2026.
Our team is outstanding. They execute really well. We have differentiated science, and as we've said, the capital is there for us to pursue it. So we very much look forward to future updates from Sionna's progress and future success. But a reminder, our goal is to transform the treatment paradigm in CF. Thank you.
Thank you.