Hello? Yep, great. Great. Good afternoon, everyone. My name is Eric Schmidt. I'm one of the Analysts at Cantor, and it's my pleasure to welcome everyone back to our conference. Delighted to introduce our next presenting company, Sionna Therapeutics, and also delighted that we have with us today Mike Cloonan, who's the company's Chief Executive Officer, and Elena Ridloff, who's the company's Chief Financial Officer. Mike, Elena, thank you and welcome.
Thanks, Eric.
Mike, maybe you could just start with a couple of minutes overview on kind of state of affairs at Sionna, and we'll get into things from there.
Yeah, great. Well, thanks for letting us be here today, Eric. Really appreciate the time. Good to see everybody. So where are we today with Sionna? Maybe just start a little bit of the history too. So, as you know, Sionna is focused on cystic fibrosis. We're going after a differentiated target from the current standard of care. We've made a lot of progress this year. The most recent that we announced was a little over a couple of months ago where we finished up the Phase 1 studies for our two NBD1 stabilizers, which was the differentiated target we're going after. We were very pleased with the Phase 1 outcome. Both compounds exceeded our targets that we had set ahead of the Phase 1, both in terms of the PK and exposure, and were also well tolerated.
We're going to be advancing both of those compounds now into the next stage. One of our compounds, SION-719, is going to advance as an add-on to the standard of care in a proof of concept study, which I'm sure we'll talk more about. Our other compound, SION-451, is going to advance as our anchor to a proprietary dual combination where we think we can drive the next transformational improvement in CF with our own proprietary tool. That has just started a healthy volunteer dual combination study that we announced last week. Both of those studies are on track to read out in mid-2026. We will be initiating that Phase 2a later this year, and we'll make that announcement when that happens. Everything's on track. We've made a lot of progress recently.
Really super excited to share the story with you today and talk more about it.
I know we're going to get deep in the weeds, but before we do, maybe just give us the lay of the land in cystic fibrosis. What is the unmet need? What is the size of this market? What gap do you hope to fill?
Yeah, so the size of the market, it's about $11 billion market today, growing to $15 billion in the next three to four years in the near term. And as many people know, it's a monopoly. Single player, Vertex dominates the space. They've made significant improvements in CF. We give Vertex a lot of credit for what they've been able to do. It's really a great success story. But the unmet need continues to be high. As good a drug as Trikafta, which is the standard of care today, the unmet need continues to be high in CF. And you can look at that through multiple lenses. You can look at it through quality of life, life expectancy. But one of the things we are very focused on is getting as many patients to normal CFTR function as possible.
We know for the patients that are on the standard of care, only a third of those patients are getting to normal CFTR function, so with our programs, we have the ability to drive more patients to normal, which ultimately should be the goal of providing more medications and treatment options for patients and specifically getting more patients to normal, so not only would that be tremendous and transformational for patients to have potentially new, more efficacious options, it's a very sizable commercial opportunity, right, given the size of this space and that it's $11 billion and growing with a single player.
Maybe let's just try and put a finer touch on that, almost a face to what it means to be a patient who's not at normal. What is life like for those patients?
Yeah, so I mean, it varies, right? So patients have different responses, but what we do know is there's a strong correlation between sweat chloride, which is the biomarker of CFTR function, and life expectancy and quality of life. And that is something we actually share. I mean, Vertex is actually saying the same things as we are, that getting improved sweat chloride is really important for long-term outcomes for patients. There's a lot of data that supports that. Obviously, we also believe we can drive FEV1 improvements, lung function improvement as well. That is what we're going after, is both moving sweat chloride and FEV1, but it's quality of life, it's life expectancy, and exacerbations, all the things that would come with a CF patient's daily living. And so our goal is to improve that and provide more options as best we can.
And then maybe, Elena, you can update us on the company's cash, cash runway, and some of the key milestones that we should keep an eye out for.
Yeah, so we ended the second quarter with $337 million in cash. That takes our runway into 2028. And we just started, we announced last week, a dual combination study evaluating both of our healthy volunteer dual combinations and healthy volunteers of SION-451 or NBD1 with complementary modulators that will read out mid next year. And we'll also be initiating our Phase 2a proof of concept study later this year, which will also read out mid next year. So we have cash runway extending beyond 18 months past our big milestones that we'll reach out read out next year.
All right, let's get into it, Mike. What is NBD1 and why does it matter?
Yeah, so it's a great question. NBD1, if you think about, let me talk a little about CF for a second. So we know what causes CF, right? It's genetic mutations to the CFTR gene that impacts the CFTR protein. And when you look at the CFTR protein, there are different regions or domains of the protein. NBD1 is one of those regions or domains. What we know is that the number one genetic mutation that causes CF is F508del. That's about 85%-90% of patients have a form of that mutation. That mutation resides within the NBD1 region of the protein. And what the mutation does is it causes NBD1 to irreversibly unfold at body temperature. So it's creating this instability in NBD1 and thereby the protein that cripples the folding, the trafficking to the cell surface, and then the overall functionality of the protein.
Why NBD1 is so important is biologically, this is a target that is well known. It has been studied in the past, but for a long time, it was considered undruggable, and mainly because of the very shallow binding pockets that existed around NBD1. Several companies have tried and failed to drug this target. We now have multiple compounds going after it. What we know is with the preclinical data that we have, we can see that the benefits of NBD1 is if you could pick any part of the protein to correct or stabilize first, you would pick NBD1. It creates the highest level of correction to the protein. If you want to get patients to normal, correcting NBD1 is critical.
And so, in our preclinical data that we have, the power of NBD1 is such that if you could correct NBD1 by itself, it has a similar level of correction to the triple combination of Trikafta, which is three compounds. So the single NBD1 compound, nearly equivalent to the triple combination of Trikafta. And for us, that's great to be equivalent or near equivalent to Trikafta, but what we want to do is raise the bar, drive more clinical benefit for patients. The way we can do that is through combination. So if we can correct NBD1 plus one other part of the protein, add a second compound, we have the potential to fully or deliver fully normal CFTR function, wild type levels of CFTR function. This hasn't been an option until now, right?
Again, I don't think you'd hear anybody refute the biology and the power potential of NBD1, but now we actually have drugs at this target.
Okay, so the biology is kind of obvious in some ways. It makes a lot of sense. Everyone should be targeting this domain. Why hasn't anyone had success previously and why should we believe you can?
Yeah, it's a great question, and so when you think about part of this is the history here behind Sionna's programs, right? Because we get asked a lot, how did you crack this? How did Sionna crack it when you've got Vertex in this space and other big pharma? Pfizer took a run at this space in the past and nobody's been able to crack it, but you have to think about the legacy that came before Sionna, so we spun out of Sanofi back in late 2019, but the science goes all the way back to Genzyme. So we've been working on this target now for over 15 years between Genzyme, Sanofi, and Sionna, and really what changed, right? How did we crack this? The challenge has always been sort of the chemistry of attacking this target.
The very shallow binding pockets make it very hard to find an opportunity to bind. The chemistry is challenging. But where we turned the corner back through that legacy was that we turned to a very structure-based biology approach, right, to crack this NBD1 nut. And that structure-based biology really helped us identify exactly where and how we were binding to the NBD1 target. We used a fragment-based approach and built up these compounds atom by atom. And we were able to leverage that you may know the CF HBE assay, which is the gold standard assay in CF, to identify which compounds had the most activity. But it really was a 15-year journey of lessons learned. The traditional means of high throughput screening were not successful here. The SAR is very steep. And so one atom changes, you can fall off a cliff. And so it's very, very challenging.
But again, I look back on the history, we wouldn't be where we are today without the level of investment, the perseverance, and that strategic shift that was made to a structure-based biology approach to NBD1.
Are the molecules you've constructed particularly large and complex, and what do we want to say about them?
They are. They're small molecules, right? But I would say they're complicated, small molecules. And that's challenging to develop them, but also creates a competitive advantage in many ways, right? They're not simple molecules to work with and develop. As I said, that SAR is very steep. But we've got multiple programs now going after NBD1 in both 719 and 451 and even others deeper into the pipeline.
Earlier, Mike, you mentioned sweat chloride and the correlation with absolute FEV1 in particular, but well, first, well, I don't know if there's anything else to say on that front, if so, go ahead. But we also want to hear about the CF HBE assay and how that correlates and fits into the development landscape for what you're trying to do.
Yeah, I mean, I'll just do a quick synopsis of the sweat chloride to FEV1. Historically, there has been a strong correlation, a linear correlation between sweat chloride, which is the biomarker of the CFTR protein function, to FEV1, which is a measure of lung function. And transitioning to the assay, the assay measures chloride transport. This is, as I said, the gold standard in vitro assay in CF that was developed by academics. Vertex uses a model of this assay, as do we, very similar approach to how we model this assay. There's a lot of validation that has occurred with our assay as with theirs. But what the assay helps you do is, chloride transport is measured. That can be translated to sweat chloride and thereby FEV1.
And so it's given you this very strong predictive tool as to what you think your compounds can do when they get to the clinic. And the way we know that this assay is very powerful is really a couple of ways. So we have synthesized all of the Vertex compounds in our lab. We've run those compounds through our assay. And when we compare the assay results in our lab to the clinical results of Vertex, they match, right? So we've demonstrated our assay is predictive of the clinical trial results of the Vertex compound. We've also done that with some of the AbbVie compounds that we've in-licensed, right? So we have a track record of being able to predict the outcomes of various compounds that have clinical levels of data.
What our assay shows us when we look at NBD1 and those combinations, I sort of mentioned this before, we have the ability to significantly improve sweat chloride and FEV1 in these combinations as predicted by the assay. Now that we have Phase 1 data, we actually have the exposure in healthy volunteers that we can map back into the assay and show where we fall on that predicted line. In that case, we have the potential to drive meaningful clinical efficacy benefit above the standard of care all the way up into wild type.
What, if any, are the limitations of that predictive translation?
Yeah, so the question we get a lot, right, is how do you know linearity continues, right? So when you look at historically, that linear projection has held up, right, up and through the proof programs from Trikafta all the way back to ivacaftor, that linearity has continued. Now we're projecting, right? We have NBD1, we have our combination, so we're projecting what that will be. And that linearity projection still holds in our model. We still see the potential for that linearity, but now you have to show that, right? We have to show that in the clinic by demonstrating this in CF patients that we will continue to drive sweat chloride improvements, and then in sweat chloride, you're going to drive FEV1 improvement as well.
So that's the projection holds in terms of what our assay would say, but now we have to show the evidence of that as we move further into the clinic.
Okay, sounds great. You've got two molecules. You mentioned both already, 719 and 451, and you're deploying them in different ways. Maybe just talk a little bit about the different pharmacologic properties of these drugs and what makes them deployable in the ways that you're seeking.
Yeah, so 719 and 451, both highly potent NBD1 stabilizers. And we were fortunate, as Eric is alluding to, when we did the Phase 1 studies, both of these programs achieved the target we had set from an exposure perspective. We didn't see any separation on tolerability in a good way. They were both well tolerated. But what we did see pharmacologically from a PK perspective is that 719 is just slightly more potent than 451, even though they're both potent compounds. And how that makes a difference is as we think about that clinical development plan that I talked about before, our first proof of concept study is going to be as an add-on to the standard of care. And at the same time, we're going to do this dual combination work with our own proprietary compounds.
When we look at each of those independent clinical paths, what we really wanted to do was leverage the differentiated profiles of both 719 and 451 to best enable that clinical strategy. And for the add-on, it's very important to think about an NBD1 compound that at lower doses can drive that efficacy that we're seeking. And our target clinically has always been a minimum of a 10 millimole sweat chloride improvement over the standard of care, which we believe is going to translate to at least three points of FEV1 as well. And so for 719, when you look at our PK curves, at the lower doses we tested with 719 compared to the lower doses we tested with 451, we achieved higher exposure of 719 relative to the target we had set. So we're higher up the curve, if you will, right?
The opportunity to drive higher efficacy with 719 at lower doses, and that's important for the add-on because as an add-on, we really want to take the lowest dose possible to add on top of what is already a triple combination of Trikafta so that we minimize tolerability, DDI, but also drive the incremental benefit, and so 719 was really the ideal fit for that path. When we think about the dual combination, it's really the inverse. What's important for that dual combination where we have NBD1 plus one other compound coming together, you want to drive the exposure as high as possible because now we're trying to get to superiority over Trikafta in our own combination, and 451, when we look at the PK, was achieved higher exposure at the higher doses we tested, so it was the ideal dual combination drug.
It just really provides strategic optionality for us and flexibility now with two different compounds that we could advance in two different ways. It really allows us to be data-driven as to how we progress from here. The prioritized path for us is the dual combination. We think that is ultimately what is best for patients. We think it is what's the best commercial path. We are also open to that add-on in the future as to whether we would develop in the future, but we're going to make that decision once we see that data.
You talked about strategic optionality. I can imagine commercial considerations are in your mind, pricing, etc. Maybe you just want to share with us more explicitly your thoughts.
Yeah, correct. I mean, when you think about that strategic optionality, Eric's right. When we think about that, as we said, we're going to do the add-on with one compound and the dual combination with 451. When you're having two compounds provides this flexibility because if we do decide at some point to commercialize both paths, now you have two different compounds moving in two different directions with two different profiles and the ability to price them differently, right? And so when you think about the difference between pricing an add-on on top of a therapy that already costs $350,000-$400,000, you have a little bit less pricing flexibility in that add-on scenario as opposed to your own dual combination where you can price it differently, right? And now you're not worried about the same compound being priced two different ways and two different labels potentially, right?
This gives us a lot of flexibility to think about that, and we really like that opportunity.
Maybe let's get a little bit more into the data. I don't know if you want to start with one or the other molecule, but you did complete two Phase 1 studies. What'd you learn? Safety, efficacy, you already alluded, of course, to the assay results, but anything else remarkable?
Yeah, so the Phase 1 was really designed to do two things and to learn a couple of things. One is the PK and exposure and then the safety and tolerability, right? So PK and exposure we've talked about. When we went into this study for both 719 and 451, we leveraged the CF HBE assay to set very specific exposure targets that we needed to achieve to advance these compounds. And that's, again, the predictive power of the assay. We set the targets based on two dimensions. So one was if we added these NBD1 compounds to the standard of care, that was one target. The other was in a dual combination, that was a separate target. And it actually is the higher of the two targets because you need more exposure as part of a dual than you do as part of an add-on.
So we'd set both of those two targets. What we learned was that both compounds exceeded both targets at multiple doses, right? So again, it really exceeded our PK targets that we had set ahead of time. Translating that back into the assay, we saw an opportunity to deliver meaningful clinical benefit above the standard of care all the way up until wild type potential. So that's what we learned from the Phase 1 that helps us now advance these two programs forward. On the tolerability side, we were very pleased to see that, as I said, no real separation from the two compounds in a good way. We really saw well-tolerated small molecule programs that are both advanceable into this next stage. And so that's what we sought out to do, right? We set out to explain, can we get the PK that the assay implies?
And then, can we also see well-tolerated compounds? And then we made the decision to advance them both.
Okay, so let's talk about next steps for each, maybe starting with 719.
Yeah. So 719, we'll go into the next step as Elena was talking about in terms of milestones. The next step for us is we are completing a DDI study for 719, which is a midazolam study, which is a proxy for Trikafta. Trikafta has its own DDI profile. And so we have to confirm that we can add 719 on top of Trikafta without DDI. All of our preclinical modeling shows we have a clear path to combine 719 on top of Trikafta, but we need to confirm that with a midazolam study. Once that is completed, we will initiate the Phase 2a proof of concept study where we will add 719 on top of Trikafta. That will be a sweat chloride-based study that is powered to show at least a 10 millimole sweat chloride improvement, about a 20%-25% improvement above the standard of care.
It will be a very efficient 16-patient, two-week study, a 2A crossover design. But we will have that data, as Elena has said, by mid-2026. And that will be the first CF patient data with NBD1. So very excited about that. What that study is designed to do is really be a proof of concept, proof of biology study where we can show by adding NBD1 on top of the standard of care, NBD1 is synergistic with, but yet different from the components of Trikafta that we can improve CFTR function as measured by sweat chloride. And it's the first ability for us to show the translation of our CF HBE assay into CF patients. So very meaningful study that we'll have in 2026. So that's the add-on.
Maybe just a couple of questions there on the 10 millimole improvement that you'd be looking for. What does that translate into for FEV1?
So we predict that will be at least three points of FEV1 improvement. And the reason we set that, just maybe to back it up too, you may be thinking this, Eric, is that 10 millimoles of sweat chloride and three points of FEV1, if you talk to the community, KOLs, physicians, the CFF, and ask them what would be meaningful differentiation in terms of efficacy above the standard of care, what would get you excited, what would you view as the potential to be superior, that's what comes back. A minimum of 10 millimoles and three points of FEV1, that would be interesting to the community. Obviously, anything higher than that, even better, right? Obviously, they would want even more FEV1 if we could deliver it, but that's the minimum bar that we've set. And this study is just sweat chloride, right? It's just a sweat chloride-based study.
The FEV1 will come in the later stage studies. We will include that, obviously, as part of our design to drive that incremental benefit in FEV1.
You enroll a population that's not achieving a proof of concept?
Yeah, so these patients will be on physician-prescribed Trikafta. They'll come in already on their Trikafta. They'll be stable on their Trikafta. And if you think about it, who we will enroll, we'll have sweat chloride criteria. We're not going to enroll patients who are already at normal or below 30 millimoles. So they're already at normal. And we won't enroll sort of the almost non-responders, if you will, right? Because is there something biological there that may be causing that? So we will have people who have had a response to Trikafta, not yet at normal, and they come in on a stable dose of Trikafta.
You think that's a majority of the population?
Yeah, if you look at what the distribution of that curve, like we said, only a third of patients are normal on Trikafta today. So two-thirds are not. And they do tend to cluster in a certain range that you see on some of the post-marketing data that exists out there. So we have a good sense for what that sweat chloride criteria should be.
Okay, maybe continue with 451.
451, yeah. So do you want to take that one? We'll take 451.
Sure. So the next steps there is 451, as Mike mentioned, we want to advance that as part of our proprietary dual combination. So we have two potential dual combinations that we're currently evaluating in a phase 1 healthy volunteer study. So these are both independently, they've all been tested in phase 1, but we want to look at the dual combinations together to look at their safety and PK combined before we go into later stage studies in CF. So that study is ongoing now, and it's looking at 451 in combination with SION-2222 and 451 in combination with SION-109. So those are two of our complementary modulators. And again, there we're looking at PK, safety and tolerability of those combinations to then choose which of the dual combinations we advance into later stage Phase 2b dose ranging studies in CF.
So Elena, what gives you confidence in the complementary modulators that they are of good enough quality to do their job in this combination?
Yeah, so that's a great question. So as Mike was talking about the assay, we've also looked at all of our complementary modulators in the assay and see their similar efficacy when we look at them in combination with our NBD1s. We've looked at all kinds of permutations. So we look at, as Mike talked about, adding on to Trikafta, standard of care, looking at our own combinations. And what we see in the assay is that we can get to full CFTR correction when you look at SION-451 with either of our complementary modulators. We get to that wild type-like efficacy at max concentrations in the assay. So we think, based on what we've seen initially in the Phase 1s, that we have that opportunity to provide clinically meaningful benefit with a dual combination.
We do have clinical data. That's the same with SION-109, which is one of our complementary mechanisms. We have Phase 1 data that's similar. You hit the PK targets that we had set for that. That compound was well tolerated, combines nicely with NBD1. SION-2222 that Elena mentioned came from AbbVie. That actually has Phase 2 level data, right? So we in-licensed that compound for a reason. It actually has a good amount of clinical data, safety and tolerability data. So we have a good history now with that compound that it combines nicely and has shown the ability in certain combinations to move both sweat chloride and FEV1 in CF patients. So we actually have real data on that program.
What are the timelines then for the combination approach?
Yeah, so that initiated last week, and that data set will also report out mid-next year.
At which point you'll make a decision on which to go forward with, and then the next steps will be in patients.
Dose ranging.
Dose ranging.
And what's your target product profile here? You mentioned with the add-on, it's obvious you just got to beat Trikafta. What are you trying to do with the dual?
Yeah, it's the same. So the clinical target that we have with an add-on or the dual combination is superior, right? And as you said, it's obvious when you're adding something on top, you got to be better than the standard of care when you're adding that compound. The dual combination is also targeting the same profile. We want to deliver at least a 10 millimole sweat chloride improvement over Trikafta as the baseline, and then also three points of FEV1 as a minimum, right? So the clinical targets, minimum clinical targets are the same. How you get there is slightly different, right? Whether it's a dual combination or a quad.
But in the dual combination, we believe if you can deliver that level of a profile, that's very meaningful for patients, for the community to have a dual combination that can compete directly with the triple combination of the standard of care. And if you're driving incremental sweat chloride and FEV1 improvement, that's very meaningful.
We've just got a couple of minutes left, but Mike, what's it like operationalizing studies in CF these days? You mentioned Vertex has had a monopoly for a long, long time, and you're going up against the monopoly. Are you viewed as a welcome entrant, or is it particularly difficult to get into these centers?
Yeah, so I'd say the first CF study we're running is about to happen, right? That's the Phase 2a proof of concept that will start later this year. But the beauty is, I'd say there's two things that have really manifested itself as we've advanced these programs. One is the unmet need that you've asked about, the desire for more options in this space, right? Despite the fact there are good options, but we think we can do better and do more. So when you think about the CFF, right, the Cystic Fibrosis Foundation, they are very critical for a company like Sionna to establish ourselves. They have a network, a Therapeutic Development Network, which is all the clinical sites that they work with, and they can help us position our program with these sites. They provide funding to these sites in many cases.
So they are really a great ally and partner in this, right? And they're looking out for the community and the patients. They want what's best for the patient. So when you're entering a space like this as a new entrant where there is an established competitor like this, the CFF is critical, and they've been a great partner for us from the beginning, even all the way back to the Genzyme days and are very supportive of the approach and the biology of NBD1. So that's critical. I think it's also the team that we've brought in, like Charlotte McKee, our CMO. Charlotte worked at Vertex. She was the head of clinical development at Vertex and developed most of the approved modulators there as well. So she's very familiar with the community, the clinical trial sites, the KOLs.
And so that's very, very helpful when we think about the capabilities that we have, the relationships we've built. And now we're in a good position right now. The receptivity to this Phase 2a from the sites has been very positive. There's been a lot of energy around wanting to be involved in this Phase 2a study. And we're looking forward to kicking that study off soon.
Mike, Elena, thank you so much for sharing the story with us.
Thanks for having us, Eric. Good to see everybody.