Happy to be here moderating a fireside chat with Sionna. Maybe to kick it off, Mike, if you want to just give a quick overview of the story, maybe introduce the team, and then we can do Q&A. Sound good?
That's great, Paul. First, thanks for having us. And Steve, always great to see you and to be at the conference. Thanks for everybody for being here today. So I'm Mike Cloonan, the CEO. Maybe as a quick background on Sionna, many of you would know we're focused on cystic fibrosis, but we're going after a differentiated target called NBD1, which I'm sure we'll get into. Our goal really is to transform the standard of care and revolutionize how CF is treated today. Despite the great advancements that have been made in CF, and we give Vertex a ton of credit, there is still a high degree of unmet need that exists in this space. And one of the ways we will talk about unmet need is it could be quality of life, it could be life expectancy, but we focus a lot on getting patients to normal CFTR function.
We know today that only a third of patients on the standard of care get to normal CFTR function. With NBD1 and with our combination strategy, we have the ability to drive and the potential to drive more patients to fully normal CFTR function, which we think is ultimately the goal. Ultimately, we want to drive more options for patients. In a $11 billion market today that is dominated by one player and growing to $15 billion, more options for patients are needed and more differentiated options, and that's really what our goal is. If we can do that and if we can potentially raise the bar from an efficacy perspective, not only would that be great for patients, but it's a significant commercial opportunity as well. We are in a really good place with this differentiated approach that we're taking.
We'll talk about the strategy, I'm sure, later on today. The two quick updates is that we're in a very good place in terms of our programs. We're taking two NBD1 stabilizers forward right now, which we'll get into, I'm sure, in more detail. 719 has advanced into our phase II a proof of concept study, the PreciSION CF study, where we will add 719 on top of the standard of care. It's a sweat chloride-based approach where we look at improving CFTR function and demonstrating that NBD1 truly is differentiated from the components of Trikafta, but also synergistic with those components of Trikafta. That data we expect to have in mid-2026. At the same time, we have started our healthy volunteer dual combination study where we are advancing 451, our second NBD1 stabilizer, in two different combinations.
One is with our Sion-2222 compound, a TMD1 corrector, and the other combination is with Sion-109, our ICL4 corrector. We'll have that data, that's a healthy volunteer study where we'll have PK, exposure, safety, and tolerability, and we'll have that data by mid-2026 as well, with the goal of selecting the best dual combination that we would advance. Our prioritized strategy is this dual combination that we'll get into later. We think that is ultimately the best profile for patients and the best commercial opportunity. We have this unique opportunity to leverage two different assets in two different ways to optimize the clinical development strategy.
Great. Maybe let's start and talk about the phase IIa study, the design of it. What can we learn from it if the data are positive, and what are the limitations going to be of this trial?
Yeah. Charlotte, you want to take that one?
Yeah. Charlotte McKee, the Chief Medical Officer. You have heard about the study design. It is a two-way crossover study. It really is intended as a really efficient, relatively rapid way to prove the NBD1 hypothesis, to prove the biology. It is a proof of concept, proof of mechanism study where patients will come in on a background of stable Trikafta per standard label dose, and they stay on that through the whole study. They will get two weeks of our NBD1 at a relatively low dose, 719, and two weeks of placebo. They will not know which period they get which, but then the readout will be safety, tolerability, and also the change in sweat chloride in their period when they get 719 on top of Trikafta versus the period when it is just Trikafta alone.
What that really will tell us, just to reiterate what Mike said, is that it will show that NBD1 does something truly different, is unique mechanistically, differentiated from the standard of care, which is represented by all the components of Trikafta. It will show us, as we predict, that there is substantial CFTR function still to gain in patients when they are stable on the standard of care when you bring NBD1 to the table. It will also be the first time that we will be able to directly correlate our predictions in our own CFHBE preclinical assay with clinical outcomes in people with CF via CFTR function. We think that will really help us actually, first of all, enroll in the next phase of the studies, which we are planning to be our dual combination dose ranging studies.
Those are going to be longer, and we think that'll be a really important proof point at that point.
Yep, yep. How have you thought about the bar for what is good? I know you've talked about, maybe I'll just kind of even preface it a bit more. I know you've talked about this 10-millimolar bar, which makes sense based on some historical data. How does that bar actually tie back to the dose you've selected and what level of efficacy you'd predict at that dose? Ten can be clinically meaningful, but is 10 also validating of the predictiveness of the assay?
Yeah. Why do not I take the real quick on the 10-millimoles target, and then we can talk about the assay translation. As Paul said, our target, and as Charlotte mentioned, in that phase IIa proof of concept, the target is at least a 10-millimole sweat chloride reduction. We also think that even though that study, even though that phase IIa study is not meant to show FEV1 movement, it is really a sweat chloride-based test. If we can move sweat chloride to that degree, in the future development plan that we would have, we would also anticipate movement in FEV1, something on the order of three percentage points of FEV1 improvement if we hit that level of sweat chloride.
As you said, Paul, the precedent for that bar, 10 millimoles of sweat chloride, three points of FEV1 improvement, that has really historically been the clinically meaningful bar that people have set. That goes back to Orkambi and Symdeko, sort of that early programs that were out there with a very similar profile. It also comes from us engaging with the community. Now that Trikafta and elexacaftor are on the market, we've asked the question, what is meaningful to you above the standard of care? You have a baseline threshold now for response to Trikafta and elexacaftor. What above that would be meaningful? It consistently comes back, what would be meaningful as a minimum bar is this 10 millimoles of sweat chloride and, again, FEV1 improvement.
That is very, very consistent, which is why we've powered the study to that level and why we feel like if we achieve that, that is meaningful to the community and advanceable right from there. Charlotte, do you want to talk a little about the translation and how we think about that?
Yeah. So we use that CFHBE assay in a wide variety of ways. It is, first of all, important qualitatively. That 10 millimolar bar per liter of sweat chloride, not only is it where the clinically meaningful bar is, but it also is very clearly outside of the noise. When we, over the years, our researchers run hundreds and hundreds of replicates of our CFHBE assay. When we look at what zone we predict that we'll be in, 1, 10 as the minimum bar and anything above that is clearly showing us what we see in the HBE assay, which is there's something very different. That is one reason why it's important. We're translating on a quantitative basis, and we do have predictions, zones, and that anything above 10 is solidly in the qualitative zone that we've predicted based on the CFHBE assay.
Yep. Okay. I think the interesting question is kind of like, how do you take these data and map it onto your assay and then also another drug? Going back to the whole question around the dose, I think it's important because how did you pick the dose? I guess is the thesis here that if you see 10 with this dose, there's still a lot left over in how much you can push the pharmacology?
Yeah. This is in the PreciSION CF study, the phase IIa that Paul is asking about in terms of that dose, because this is the first one in CF patients. We have not stated what that dose is yet, really for competitive reasons. What we have said is that we are picking in the lower dose range that we have tested for 719, which is the compound we are taking into the PreciSION CF study. The reason we picked this lower dose for that first study was really threefold. First, if you look at the PK of 719, and we did multiple doses that we tested in the phase I, we exceeded the add-on target exposure required as inferred from the assay at the lowest dose we tested, which was 20 mg BID.
Every dose we tested higher than that, even more, we exceeded even more of that target. When you look at NBD1 being added to three components already, NBD1 does not need to do that much work. You do not need that much exposure from NBD1 to drive that minimum bar of 10 millimoles of sweat chloride. For us, we could take a lower dose of 719 and still achieve that clinically meaningful bar that we have set and even exceeded. That is one of the first things. The second is we are adding a fourth compound to an already defined profile of Trikafta. Trikafta has some limitations, black box for LFTs. Adding a fourth compound at a lower dose, we feel like gives us a better opportunity to not add to that tolerability profile.
The third reason why we picked that lower dose was the DDI profile of Trikafta. As many of you may know, the components of Trikafta are all CYP substrates, and ivacaftor is a sensitive CYP substrate. Our goal was not to have any impact on the exposure of Trikafta by adding NBD1. As you know, Paul, we did the DDI study to confirm that. We picked multiple doses in this DDI study to confirm we can use 719 on top of Trikafta at the labeled dose of Trikafta and be certain that we're going to have a true study to measure NBD1's impact on Trikafta. Those are the three reasons we picked the lower dose.
When you think about the translation, like you said, as we have a model that can help us translate the add-on to Trikafta model at that dose, we have a dose response curve, and we know based on the exposure we can achieve where we will end up. It is the same model we're using for the dual combination. It is just a different dose, as you're saying. We have a different dose response curve for our dual combination, which is just two drugs that shows us where we need to be from an exposure perspective to drive that clinically meaningful benefit. Because the target, whether we're going as an add-on to Trikafta or in the dual combination of just two compounds of our own portfolio, the clinical bar is the same.
We're still trying to achieve a 10-millimole sweat chloride improvement above the standard of care, which we believe will translate to FEV1 improvement. The exposure targets are different. Because again, in a quad, four drugs, your exposure of NBD1 is less. When it's two combination drug, NBD1 has to do more of the work, and the exposure will need to be higher. With 451, we're going to be at higher doses when we go into the dual combination. Does that make sense?
Yeah, absolutely. How are you selecting patients for this study, and do you think you'll see anything on FEV1 or another functional parameter?
Yeah. So we obviously have eligibility criteria for this study, and it's an early study, so they're relatively rigorous. I guess to unpack what you're asking, there is a sweet spot in terms of sweat chloride, since sweat chloride is the primary activity endpoint of this study. So we do have eligibility criteria. We know what the distribution in actually from the Cystic Fibrosis Foundation, we actually have a good read on what the distribution of sweat chloride is in patients who are on Trikafta. We're certainly looking for patients who are not yet normal, do not have normal CFTR function on Trikafta, but also those who are not outliers on the higher end of sweat chloride, who had no movement at all in sweat chloride. Because not to say those patients looking forward might not respond.
They may respond to an NBD1 modulator, but those aren't the patients we're looking for in this trial. We have eligibility criteria in what we consider sort of a sweet spot dynamic range.
Okay.
On FEV1, do you want to talk about CFTR?
Yeah. So really, FEV1, the study is not designed in any way to look at FEV1. It's a two-week study, which is really nice and efficient for sweat chloride. You do need longer, really, to see FEV1 plateau. Even more importantly, you actually need larger numbers to be powered and to be out of just the variability range of FEV1. We do not have any expectations for FEV1. As Mike said, really, we're looking to be substantially out of the noise in terms of moving CFTR function. If that happens, as we predict, then we really do predict that FEV1 still has room to improve.
Yeah. Okay. Okay. If these data are positive, with what level of confidence can we draw a line from 719- 451?
Yeah. This will come back to the assay in terms of your question. We have this, as Charlotte said, this 16-patient two-way crossover. Each patient becomes its control. We'll take exposure reads and concentration reads for every patient. We'll look at how that patient responded from a sweat chloride perspective, what concentration did they achieve of NBD1. In many ways, we can look at patient-by-patient response and look at the assay and how that would have predicted that patient response because it is all concentration derived. That will give us the confidence, depending on what level we hit of sweat chloride, to be able to say at the macro level, okay, you want to at least have achieved that 10-millimole sweat chloride to have a successful study.
We can start to pull apart the patient-level data to help us make the prediction for the dual combination. Because again, it's in the same assay, and it's all, again, dose response, concentration curves. We can sort of really tighten up the assay as we think about going to the dual combination based on what we learn in the 719 add-on. There will be this direct translation that we can make. Even though they are different compounds, they're both NBD1 stabilizers, and the impact is very similar in the assay. It's just different doses. As we mentioned, you're going to have a different dose for the 719 add-on than you're going to have for the 451 dual combination. We have all of those predictions already in hand, and we can map back now with actual patient data to confirm that prediction for the dual combination.
If you actually ended up seeing something that was even better than you expected in this phase IIa, would you consider advancing that for combo?
Yeah. It's a great question. We get asked that a lot. Would we advance the add-on if we had a successful study? It really comes to the way we look at it, Paul, is if we have a positive study, if we achieve the 10 millimoles of sweat chloride at this dose we've selected, that could be a possible advanceable program. Successful study, you're showing improvement in sweat chloride to that level, and we think eventually it will translate into FEV1 in later stage studies. That is advanceable. We've always said the best profile at this stage is that dual combination. You have two drugs coming together. The tolerability profile may be better potentially than what's out there today. You have the ability to drive potentially to wild-type levels of normal CFTR function with a dual.
To your question, it's more about if that is a successful study and we hit that mark of clinically meaningful, it's really a capital question. It's more about can we raise enough capital to move two programs into dose ranging and into phase III. What we haven't wanted to do is to commit to that yet until we see the study and is it successful, and then would the capital be there and is the support there from the community to say, "Hey, that's something we would want." I actually think it's a very legitimate question that you've asked, and I fully expect if it's a successful study, that could be something that the community does want. It would come down to can we fund and develop both of those paths.
We wouldn't want the add-on necessarily crowd out the dual because that's obviously going to be a priority for us.
Of course. The more options are better.
Exactly. That is where our head is at. It is really fundamentally a capital question.
Yep. Yep. Okay. Makes sense. For 451, how are you going to pick which drug to combine it with?
We already selected what we considered our preferred complementary modulators from our portfolio. That was based on a wide variety of criteria. First and foremost, the metabolism profiles, they actually are differentiated. The two complementary correctors are, as Mike said, galicaftor or 2222, which is a TMD1 corrector, similar in terms of mechanism to tezacaftor and lumacaftor in the approved modulators. Then Sion-109, which is an ICL4 directed corrector. Both of those are interface domain correctors. Based on the biology of F508 deletion, CFTR, either one of those when combined with 451 actually has the potential to normalize CFTR function. Each of them mechanistically is a really good choice. It's really going to come down to how the actual compound performs. That's really why we're doing the phase I healthy volunteer dual combo study.
Yep. Yep. Okay. Can we go back to the assay for a bit? I think one thing that this is not a Sionna specific thing, but just one difficulty for any public market investor that does not go under deep CDA is how do you really vet the methodology of preclinical work? What do you say to someone who is kind of like, "Hey, look, we have seen companies say they have good preclinical data in CF before." How do we actually scrutinize this and sort of verify that it is methodologically sound and done in the same way that has been predicted for Vertex?
Yeah. It's a great question, and it's an obvious one. For the history, as you said, we know that there has been a history of CF companies that have tried and have showed some interesting data, yet it didn't play out in the clinic, and they've had some failures. You do need to peel those back a little bit and really understand why those failures happen, and we can talk about that. If we go up 10,000 feet at the assay, let's talk about the assay for a second. Why do we have such a high degree of confidence in our assay and that it is clinically predictive? It really comes down to three or four key points. The assay was created by academics. This was not created by a singular company, Vertex, Sionna. We leveraged this assay that was created by the academics.
There is a protocol that exists on how to run the assay. It does take expertise and precision. But our team, as you remember, from a historical perspective, our science goes back to Genzyme. We have the team that's been working on this for over 15 years. In this assay, from Genzyme to Sanofi and into Sionna, we have a lot of expertise as it relates to the assay. The other point is that there is a lot of literature out there now publicly on how the assay is run, including Vertex. They've published a lot of information on how they run the assay. We've clearly looked at that, compared it to how we run it, and they are very, very similar. You can never say identical because you don't know inside the four walls exactly what Vertex does. We only have what's publicly available.
Everything that's publicly available, we run the assay very, very similar to Vertex. One example I can give of that, that one of the things that we think is a very important part of the precision and the predictive power of the assay is the addition of human serum. You know this, Paul, but we add 20% by volume human serum to this in vitro assay that more closely can help us represent the in vivo experience. This, we think, really does help the prediction by adding the 20% by volume human serum, which is the same as Vertex. That is a public statement in terms of what Vertex does, very similar to what Sionna does. The other thing is sort of the proof in the pudding. Sionna has synthesized the Vertex compounds in our lab.
We've run those compounds through our assay, and we have replicated the published clinical results of the Vertex compounds in our assay. We have data that shows our assay prediction is this. The published clinical results are that, and they match for the Vertex compounds. We've done that with even the compounds that have failed historically, as Paul mentioned. There's Proteostasis and then AbbVie. Their triple combination was not successful. We could have predicted failure as well, as equally predictive of successes. To me, that's a powerful thing when you can say, "Hey, it's just not all the winners that you've been able to predict.
We could have predicted why certain companies did not get there. When we peel that onion back, that question of, "Why did not these other companies succeed?" In both the case of Proteostasis Therapeutics and AbbVie, it really is more about the compounds failing, not the assay. When we ran certain compounds before we did the AbbVie deal, we ran some of their compounds through our assay. They actually had a very active dual that would have been competitive with Orkambi and Symdeko at that time. Unfortunately for AbbVie, the bar got raised when Trikafta was launched. They had to come up with their own triple combination that could be competitive. Their dual actually is very active in the assay, and it matches the phase II data that is published on those two programs. You have to peel it back. That was not an assay failure.
That was actually that third compound failure that they could never get the efficacy of Trikafta. That could be an exposure issue. It could be a tolerability perspective. When you really peel it back, our view is these are not failures for the assay. You can run the assay if you really are precise. You know the right assumptions to put in there, and you validate it. You do not just drink your own Kool-Aid. We have done that through, as I said, running through the Vertex compounds and non-Sionna compounds. The last thing we have done is validated externally. The Cystic Fibrosis Foundation is a great partner and collaborator of ours. They have a lab where they run the assay as well. We have confirmed the assumptions that we use in terms of concentrations of ETI, etc. We use the same assumptions that the CFF does.
There's a lot of validation you can do to gain that comfort. That's what we've tried to articulate when investors ask that question. It's tough to get all the way under the hood. There's a lot of rigor behind this, and there's a lot of evidence behind what we have. The last thing that Charlotte mentioned is every time we do something with NBD1, whether it's the CFHBE or in other assays that we run, NBD1 is doing something fundamentally different. That ties back to the biology of NBD1 and why it's so important. In the assay, NBD1 is very, very powerful. You can see even as a monotherapy in our assay, a single NBD1 compound is nearly equivalent to the triple combination Trikafta, a single agent nearly equivalent to the triple.
We need to add one other complementary mechanism, and we have the potential to get up to wild-type levels of CFTR functions. That speaks to the power of NBD1, and that's what we want to play out. Now we've got to show that in the clinic, and that's what that first PreciSION CF study will help us show, translate back to the assay, and then we're off and running.
Yep. Yep. Okay. If the phase IIa is positive and you move forward with a 451 combo, how do you envision the development path? Is it possible to run a placebo-controlled study? Does it have to be head-to-head? Is that a superiority trial? What are the different things you're considering?
I would say it's early days. We will obviously be deeply engaging with regulators on all those questions. I think at a high level, what we're expecting is, one, the development path and the registration path is actually, we think, pretty clear. We do expect FEV1 to be the registration endpoint, as it's been for every modulator that's approved. Our goal, as you've heard, is we expect to be better on FEV1. Once we start generating data that puts us in that position, that opens up a lot of conversations with regulators. Not only does the community want alternatives and definitely alternatives that are better, but the regulators do as well. CF is a world where there is regulatory flexibility potentially. We expect to have something that can be demonstrated to be better on FEV1. That doesn't require placebo-controlled studies.
We do expect that the development path will look a little bit different than the Trikafta path.
Maybe a superiority trial?
Yeah. Oh, absolutely. I think that is what we're sort of expecting. How we get to that, randomized switch, randomized designs. There are very well-described study designs where you can show that. We think in collaboration with the regulators, that will be very doable.
I know the plan, obviously, the aspiration is to be clearly clinically better. Is there a way you can run a development program so that if you're not, let's say you trend better, but you're not statistically better, that you still have a drug given that? Because I think some people say, "Okay, the Vanza switch hasn't gone well." I look at this as it's a little bit different because it's a different mechanism of action. We've seen across many other indications that something that's different, even if it's only slightly better, is maybe more valuable than something that is functionally the same and barely. You know what I'm saying? I don't know if that's a needle that's threadable because I understand a non-inferiority trial requires such a bigger patient burden. What's your thought there?
I'll maybe start. But just from a developing the drug perspective, none of those are unfeasible. This is not hypertension or heart failure. So the numbers, even for a non-inferiority trial, are very achievable. That's not what we intend. But I'll.
Yeah. I think it's what you're saying, Paul, which we fundamentally agree with, is the need for more options is high. If you talk to the community, they would welcome anything that is fundamentally different mechanistically and would give them new options because, as we know, not every patient responds to every medication the same way. They want more options. Depending on how this data plays out, everything we see today shows that we could have the potential to be superior. If you have that potential, that's what you should execute in terms of a clinical development strategy, as Charlotte laid out. Now, as the data plays out, if there are other strategies that we think make more sense for us to do to drive more options for patients, we can evaluate that.
But all the data that we have today, again, shows that NBD1 is fundamentally doing something different and could have the potential to drive to different levels of both CFTR function and what we think ultimately will be FEV1. We want to design that study to show that. We'll always be data-driven. As we generate more and more data, that will better inform the clinical development strategy as well. The goal is, is kind of what you're signaling, to get this option to patients. How can we do it? That will be played out as we get more data.
Okay. Okay. Maybe to finish it off, just on your correctors, I feel like they get talked about less. What support do we have that those correctors are a solid backbone and we can kind of take that for granted?
Yeah. So with Charlotte, the two different correctors, 2222 or TMD1 corrector, we in-licensed that from AbbVie. That was one of those compounds that I mentioned were efficacious in the assay, but also there's phase II data. We have phase II data on galicaftor from the studies that AbbVie run, both in combination and individually. A fairly well-defined profile from a safety and tolerability perspective and in a combination that showed movement in FEV1 and sweat chloride. We have a pretty good characterization of what 2222 is. 109 has been through phase I healthy volunteer study, so not quite as much clinical data as 2222. What we saw was safe and well tolerated, hit the PK exposure that we targeted. As you know, healthy volunteer concentrations have translated into CF patients. It gives us a high degree of confidence.
109 could be a very effective option for us. Maybe just in the last 20 seconds, probably always worth letting Elena talk a little bit about cash runway and milestones coming up.
Yeah. So we entered Q3 with $325 million in cash, which extends our cash runway into 2028. As we talked about the phase 2a study and our dual combinations, both those studies will read out mid next year. We have cash runway significantly beyond those milestones mid next year.
Great. Awesome. Thank you, guys.
Thanks, Paul.
Thanks, Paul.
Always good to see you. Thanks everyone.