All right, awesome, so good afternoon, everyone. My name is Cory Kasimov, one of the senior biotech analysts here at Evercore, and it's my pleasure to host our next discussion with Sionna Therapeutics. We got Mike, Elena, and Charlotte all here, so appreciate you all making the time for us. I guess to start off, as I've been doing with all these discussions and the fact that we're already in December, as shocking as that is, to use this as an opportunity to kind of level set the conversation by reflecting back on 2025 and kind of speaking to the company's main accomplishments this year, and then we'll kind of start digging in from there.
Yeah, thanks, Cory, and thanks, Evercore, for having us. Yeah, starting with 2025, it's been a strong year and an impactful one for us at Sionna. I'll start really with the clinical progression and the progress that we've made there. We finished our phase I programs for our two NBD1 stabilizers, SION-719 and SION-451, and very positive data. Very pleased with the outcome of those two studies that we actually were able to progress both of them forward. We can talk more about the strategy, but we're moving SION-719 into a phase II proof of concept study in our Precision CF study where we're adding 719 to Trikafta to demonstrate that NBD1 mechanism is differentiated from the components of Trikafta, but also synergistic with those components. We believe we can improve CFTR function as defined by sweat chloride.
So that study will be powered for sweat chloride change. But a really important study, and that study has already initiated. We initiated that Precision CF study about a month ago. We're on track to deliver that data in mid-2026. So we completed the phase Is, we initiated the phase II proof of concept, and then our second NBD1 stabilizer, SION-451, is moving forward as the anchor to our dual combination strategy. We're taking that forward into a healthy volunteer phase I study where we're testing 451 in combination with two complementary modulators. One is SION-2222, a TMD1 corrector, and the other is SION-109, our ICL4 corrector.
The goal of that study is to show the PK and the concentration of the combinations, but also the safety and tolerability that will ultimately help us pick the combination that we want to move forward into dose ranging. That study has also initiated. We completed the phase Is and we've initiated the next set of studies for both SION-719 and 451. That's the clinical execution. We've continued to build the team and progress the company. The other thing that's worth mentioning is we completed the IPO back in February of this year. We raised over $219 million gross proceeds from the IPO in February, really set us up nicely from a financing perspective and a capital perspective where we have a lot of flexibility to progress the pipeline.
And the capital from that IPO gives us cash runway into 2028, so well beyond the milestones for both the proof of concept study and the healthy volunteer study, which we both expect in mid- 2026. So it's been a very impactful year, lots of progression on the NBD1 hypothesis, and now even looking forward to 2026, another very important year for Sionna and demonstrating the potential of NBD1 as a new mechanism and a differentiated mechanism in CF.
Awesome. So a lot to dig into and not a lot of time to do it. So let's start kind of big picture. Given the existing modulators are out there, all the work that Vertex has done, what's the current unmet need in cystic fibrosis and how can you address that?
Yeah, I'll start real quick and then I'll let Charlotte talk about this a little bit. So when we think about unmet need, one, first you give credit to Vertex for what they've done, right? It's been an amazing success story and the medicines that they've launched into CF have really fundamentally changed lives, which is what we all are here to do. So we give them a lot of credit for that. But when we step back, the unmet need is still high in CF. There is still a lot of room here to improve the lives of patients. And you can look at that from quality of life, life expectancy, but the thing that we are focused a lot on is getting as many patients as possible to normal CFTR function.
What we know is that for both Trikafta, the standard of care, and ALYFTREK, the new triple combination, about a third of patients get to normal CFTR function when they're on those medicines. So that means two thirds of patients are not at normal. There is an opportunity for us to push higher on the efficacy, lower sweat chloride levels, and drive more patients to fully normal CFTR function. We think NBD1 is one of the keys to doing that, and we'll talk more about it. But Charlotte, do you want to talk a little bit more about how we define the unmet need?
Yeah, and so if you think about it, it does play off of where sweat chloride is in the population. And we know, looking out over the whole history and the trajectory of the approved modulators, as sweat chloride in the populations has improved, the other sort of important clinically meaningful outputs have also improved, including but not limited to FEV1. When sweat chloride has improved enough, the quality of life, pulmonary exacerbations, and then ultimately those have translated in long-term studies into all sorts of reduced transplantations, longer lifespan. So there's a through line through all that. So we're just maniacally focused on improving CFTR function by correcting for the first time directly, potentially, the thing that goes most wrong with that F508del.
So Vertex has stated that they believe that we're hitting a ceiling with regard to FEV1, and the goal now is, and I assume you agree with this, it's to normalize sweat chloride levels. So is that something you do, in fact, agree with?
So we absolutely agree that the goal should be to get as many people to normal CFTR function as possible, and that we are very much aligned. Where we disagree, and this is an opinion, is what the data tell us about whether there's more room to improve FEV1. When we look at the ALYFTREK data, for example, versus the Trikafta data, we don't see that sweat chloride change or CFTR function change with ALYFTREK. We don't see those as having been substantial enough to truly say there's no more FEV1 left to give, as we know that FEV1 was the same, was not inferior.
When we look at the populations that were enrolled in that phase III program, and we know where the sweet spots have been for FEV1 improvement when something very different was brought to the table, it looks to us like there's room substantially to improve still.
Okay.
And importantly, Cory, on that, the mechanism of action of ALYFTREK is the same as Trikafta. The compounds are different, but the mechanism of action is the same. They're not directly stabilizing NBD1, as Charlotte talked about. So we think fundamentally we may be able to unlock additional efficacy with NBD1 and correcting the protein in a way that is different from Trikafta and ALYFTREK.
Interesting. Okay. So regarding your recent preclinical data at NACFC showing NBD1 stabilizers improve CFTR protein half-life to wild-type levels, can you kind of elaborate on what these findings mean and how this data strengthens the rationale for this NBD1 anchored pipeline?
Yeah, go ahead, Charlotte.
Yeah, so it really is another important proof point. We see this as another important proof point in the hypothesis that directly stabilizing NBD1 does something very different from what is out there in the standard of care. You're right, what our research showed is that there is the possibility of correcting or further normalizing or correcting one of the things that does also go wrong with F508del in that mutation. We know that the NBD1 domain is destabilized, the whole protein is destabilized, its trafficking is destabilized, but also once that F508del CFTR protein gets to the cell surface, it has a very short residence time, and when we looked in our research, in our assay, when we looked at the ability of the current standard of care, the components of Trikafta to stabilize that half-life, there was a modest improvement.
But as you said, we saw adding an NBD1 stabilizer in pretty much any combination has the potential to correct that to normal, and that really tells us, as we've seen with all the other orthogonal assays, this is something very different.
Right, right, right. Okay. So can you describe what led to the decision to move forward with both SION-719 as well as 451, and then why you selected to do one of them as an add-on study in CF patients with Trikafta and the other phase I healthy volunteer trial?
Yeah, so you just articulated the strategy, Cory, which is when we ran the phase I studies, we were looking to see if there was going to be differentiation between SION-719 and 451. And that could have been a tolerability separation, that could have been on the PK profile separation. But fortunately for us, as we progressed through those phase 1 studies for both compounds, they were both generally safe and well tolerated. There was really no separation on a tolerability perspective, which is a good thing. And then when we looked at the PK profiles of both of the compounds, if you remember, we had set two different targets for both compounds ahead of the phase I to help us define the efficacy opportunity of both compounds.
So, one, we had set a bar that is if we had added either one of these NBD1 compounds on top of the standard of care, what would be the concentration we would need to achieve to drive clinically meaningful benefit above the standard of care. Both compounds at every dose we tested exceeded that first target. So either one of them could have been an add-on to Trikafta based on that data. The second target we had set was a higher exposure threshold for either one of those compounds in a dual combination with one other corrector. And it's a higher threshold because now it's just two compounds coming together. You need NBD1 to do more of the work. You need more exposure from NBD1. And again, for both compounds at every dose we tested except the lowest dose, they exceeded that dual combination target.
So we really had a choice. We could have picked either one of these compounds and felt good about progressing them. But when we peeled the onion a little bit and we looked at the PK profiles of the two compounds, what we saw was that 719 was always a little bit more potent than 451. And where that really showed up is at the lower doses we tested. And so at these lower doses of 719, we were exceeding the add-on target by more than we were exceeding it for 451 at the lower target. So if you think about it almost as a mini bake-off between 719 and 451 for the two different paths, 719 won the bake-off as the best profile of an add-on to Trikafta.
And then the inverse was true when we looked at 451, where it sort of won out and its PK profile was at the higher doses we tested. It had higher levels of exposure and was exceeding the target by more than what 719 was doing at their higher doses. So it really played more nicely as the anchor to that dual combination option. So we looked at this and said, this could create a lot of strategic optionality for us in progressing two different compounds and leveraging their unique profiles in a way that would best position them to be successful in our clinical strategy. So that's why we moved 719 as the lead for the add-on and 451 as the lead for the dual combination. We really liked that strategic optionality and again, leveraging the unique differences of the two compounds.
Okay. So then now you have the phase II-A precision proof of concept trial with 719. When we see this data, I guess you said around the middle of next year, what are you hoping to learn when you get this?
Yeah, Charlotte?
Yeah. So really we set this up to be truly a proof of concept, proof of mechanism study. It's small. It's efficient. In under 20 patients in a two-way crossover study, what we intend to show is one, that NBD1, again, does something truly different and unique mechanistically compared with the standard of care. That is when adding, in this case, a pretty low concentration of that target of 719 to Trikafta, stable Trikafta, we intend to show that sweat chloride will move substantially more than what has been seen before, above and beyond Trikafta. We're powered for at least a 10 mmol/L change in sweat chloride. These are F508del homozygous patients. For the, let's just say the ALYFTREK study in phase III, that was a 3 mmol/L change in the same population versus Trikafta. We're substantial, room to improve, mechanistically distinct.
And then importantly, that's going to be the first place that we'll be correlating directly our own CF-HBE assay predictions in the patients via CFTR function via sweat chloride. So that allows us to really correlate back to the CF-HBE data too.
Are there other efficacy endpoints that you'll be evaluating within the study, like things that would help? It sounds like sweat chloride is going to characterize this as a win or not, but what else can we look for beyond that?
This is a simple, really straightforward study. We are dosing all of these patients, again, in a two-way crossover for two weeks, and so we're not really loading this study up with a lot of other endpoints. We may look, for example, in safety for FEV1, but this is a sweat chloride study, and that's what it's designed and powered for. If we improve sweat chloride the way we predict and hope, then that will also start to allow us to correlate back to historically how much you move sweat chloride and how much you would expect to see FEV1 potentially improve later on down the line.
Got it. So is the dual combination approach your preferred path?
You want to take that one, Elena?
Yeah, so it is our preferred path. We think having two drugs versus three is the best option ultimately for patients. We have, as Mike and Charlotte were articulating, based on our phase I PK data, we think we have the potential to deliver a dual that has better efficacy than the standard of care today, and so the opportunity to develop that profile is very attractive to us and something that we think would be the best option for patients.
So it sounds like you would envision this combination kind of being broadly used across the spectrum of CF patients. So how do you design pivotal trials to kind of maximize this?
Yeah. So we are very focused on optimizing to F508del. So just to be clear, this is we are focused on a population, the 90%+ of patients who make a CFTR protein. And that's the population we're looking at. When we think of it's early days, so thinking forward to pivotal and other studies, we do intend to be demonstrating the goal would be to demonstrate efficacy compared to the standard of care.
Okay. So then the other combination approaches that you have with your ICL4, the TMD1, combining with 451.
Correct.
What are the learnings you're looking for there when you get that update?
Yeah. So what we're looking for there, this is the first time we're putting these two drugs in combination together. We've done the phase I individual studies for all of these compounds. So now what we're looking for is, are they safe and well tolerated when we combine the two drugs together with 451? And we're also looking at the PK profile. What is the concentration that we achieve in combination? Because as Charlotte said, we always push back to the HBE assay. We know where we need to be from an exposure perspective in these combinations to deliver clinically meaningful benefit above the standard of care as our dual. And so we will always compare back, what is the exposure we're achieving?
And is there a separation, just like we talked about with 719 and 451, we're now looking for in these dual combinations, do we see anything different, one combination versus the other, that we would prioritize one to push forward? And that's the ultimate goal, is to leverage the safety and tolerability profile and data and the PK profiles in these studies to help us select that best dual combination that we would advance forward.
So I guess a question you're probably asked this all the time, maybe sick of answering it, is on these assays, right? Like Vertex, at least to the investment community, probably is the most famous assays on the planet, right? How confident are you in the assays that you have?
Yeah, we're very confident in our assay, and we do get asked the question a lot, and we understand it. We understand the dynamic of the CF space. There's been nobody else that has broken through in CF. There's been some failures, so we understand the nature of the question, but if you dial back the assay for a second and you think about the history, the assay was created by academics, and there is a protocol, well-established protocol on how you run the assay. It does take discipline and precision, but our team has been running this assay for over 15 years now because this generation of these programs started at Genzyme, moved into Sanofi, and then we spun out of Sanofi back in 2019, so this team has been working very closely in this assay for a long period of time.
We also know that you probably have heard us talk about this, that we have synthesized the Vertex compounds in our lab. We've run them through our assay. And when we compare our assay results to the published clinical results of Vertex, they match. And so it gives us a lot of confidence that we have validated our assay and its predictive power. And then when we look at published literature that's out there from both Vertex and others around how to run the assay, we run it very similar. You can never say identically because we're not inside the four walls of Vertex, but they are very, very similar. And our overall stance on the assay is that the assay can be run and it can be run by many different groups, right? When you look at what's really important is the assay makes a projection.
It's making a prediction of what you need to deliver. What you really have to have is the compounds need to deliver on what the assay is predicting. And I think when you look back in the history of CF and why maybe some companies have failed, I would say it's not the assay, right? People can run the assay and do it well. What has happened is the compounds just haven't delivered what the assay was projecting that they needed to do. And I think that's really the story here, is we can get caught up on the specifics of the assay. But if you step back away from just the CF-HBE assay, which is a very important tool, all of the preclinical data that Charlotte referenced before, the half-life data, we've had many other assays that we run.
It shows that NBD1 is doing something very fundamentally different from the components of the standard of care, and we think that's the biology of NBD1 and why we have the strong belief with this level of differentiation that we can do something very, very different for patients, create new options. We think the market is ripe for more options for patients, and if we can raise the bar from a clinical and an efficacy perspective, it would drive a lot of advantages for patients, and so that's what our goal is, and the assay is a tool, and we have a lot of confidence in its predictive power. The first chance we'll be able to demonstrate that is the phase two A proof of concept that Charlotte described, the Precision CF study in the middle of 2026.
So last question here for you. As you start to collect data in the middle of next year, when you think beyond that, are you willing to take multiple different combinations forward? Is it more pick one and go?
It's a great question, Cory. Yeah, I would say think about the question we get often is we have the dual combination approach, right, where we have the two different dual combos. Right now, the plan is we would select the best one, assuming there is clear separation, right, that we would pick that. The other question we do get, which is related, would we ever take the add-on combination forward, right? Would we move 719 forward as an add-on to Trikafta if we had a positive study? And what we know is that if we hit that clinically meaningful bar of 10 mmol sweat chloride improvement, that would be meaningful to patients. And that could be a very viable commercial path. But what we've said is that's really more of a capital question.
Could we raise enough capital where we could progress both an add-on approach and our proprietary dual combination? What we want to make sure is we preserve the dual combination option, but we'll obviously ask and address that question when we have the data and we'll see where the capital markets are, and if we can raise enough money, it may be a very interesting opportunity for us to have two paths available to us.
Awesome. It's going to be a very interesting 2026, that's for sure.
Thanks, Cory.
Thank you guys very much for being here.
Yeah, pleasure. Thanks, Cory.
Thank you.
Good question.