Great. Good morning, everyone. Thank you so much for joining us. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, and we're really pleased to have with us Mike Cloonan, President and CEO of Sionna. Mike, to start here, can you provide an overview of Sionna's story, including the company's history, strategy, as well as recent pipeline progress? Just given the recent IPO, I think it'll be great to level set everyone listening in.
Thanks, Salveen, and thanks first to Goldman and to you for hosting us. It's a pleasure to be here with everybody today. Yeah, let me start with the history, your question on the history of Sionna. Sionna was formed in late 2019 as a spinout from Sanofi. Our science goes all the way back to Genzyme, now about 15 years ago in the making, as to when our science originated. Started at Genzyme, moved into Sanofi, and then spun out as Sionna in late 2019. I tell, that's a great question for us because many times we get asked about, you know, we're going after this very challenging target that we'll talk about in NBD1, and we often get asked, how did Sionna, who's been in existence for four or five years, crack this very challenging target?
But it speaks to the history, right? We wouldn't be where we are today without that legacy of investment and perseverance and commitment that happened between Genzyme, Sanofi, and now Sionna, that has put us in the position to have these first-in-class, differentiated NBD1 stabilizers, which we'll talk more about. That is the history. Strategy, let's talk about the strategy. I sort of referenced NBD1. Our strategy, I'll start with the mission first, right? Our mission is to transform the standard of care in CF. We think we have a unique opportunity with these NBD1 stabilizers that are first-in-class, highly differentiated, and they really are the key to fully correcting the CFTR protein, which we can get into the biology.
If you can fully correct the protein, you can fully normalize the protein's function, and that's our goal: get as many patients to normal CFTR function as possible. The strategy is to create a combination that anchors NBD1 as the anchor to that combination, where we could drive meaningful clinical benefit above the standard of care, right? The case that we're really prioritizing is what we call a dual combination. NBD1 plus one complementary corrector put together that could drive incremental benefit over the standard of care, both in terms of sweat chloride and FEV1. The strategy is highly focused on having multiple shots on NBD1, and I'll talk about the recent data of our two NBD1 stabilizers, but we're also investing in these complementary mechanisms that you can combine with NBD1.
When you combine NBD1 with NBD1, this is where you have the potential to deliver fully normal CFTR function. We know today that even for the patients that are on standard of care, only 1/3 of those patients will be able to achieve normal CFTR function. That is the opportunity for Sionna, with these combinations that we can deliver, that we can drive more patients to normal CFTR function. Let's talk about the data that we just announced last week. We concluded the phase I trials for both SION-719 and SION-451, our two lead NBD1 stabilizers. We reported positive data on both of them, and the takeaways that we had from that was that both compounds were well tolerated, and both compounds achieved and exceeded our PK targets that we had set based on the CFHBE assay in two different ways.
They achieved and exceeded that target based on an add-on to the standard of care case, but also in that dual combination case that I mentioned before. We could have advanced either one of those compounds based on the profiles that they have achieved, but what we ultimately ended up doing was we stepped back, and when we looked at the data for the two compounds, there were some unique differences between the two compounds that we thought we could leverage that would best support the clinical development plan going forward. The choice we made, that we articulated last week, was that SION-719 is going to be the compound that we advance into the phase II-A proof of concept as an add-on to the standard of care.
The reason we chose 719 for that path was really because it was differentiated in terms of potency relative to 451. Both compounds are potent, but 719 is a little bit more potent than 451, and where that comes into play is specifically at lower doses. If you look at the PK curves of 719 compared to 451, at the lowest doses of 719, we are far exceeding the PK targets for the add-on. That is really important, and we will talk more about how the add-on will come into play from a proof of concept perspective, but that is the path we ultimately chose for 719 as the add-on path, given its unique profile. 451, we are using as the lead compound in the dual combination, right?
That is our prioritized path, and the reason why we picked 451 for that path was because at high doses, we achieved higher exposures than we did with 719. Importantly for 451, when we think about this dual combination of 451 plus a complementary mechanism, the goal is to get exposure as high as possible so that we can drive the efficacy as high as possible. Again, when you look at the comparison to 719, we got to higher exposure, well above the targets that we had set for the dual combination. This really opens up a lot of strategic optionality for us now, being able to advance both compounds in two different ways, and again, leveraging their unique profiles that we think best supports the clinical plan going forward.
We were thrilled, you know, we sort of had a hypothesis going into the phase I that one of them would rise to the top, and it would be an easy selection. As we went through the phase I, they continued to both look very compelling, and there was no separation on tolerability in a good way. They both continued to look well tolerated, and then we had this unique opportunity to advance both based on the profiles that they exhibited in the phase I.
Great. Mike, can you also speak just to the outlook for the company over the next 12- 18 months with regard to key events across your portfolio?
Yeah. So when you, so building off the phase I data, the couple of milestones that we have coming up, we have the 719 path, which is the add-on. Again, we will be advancing that into the add-on to the standard of care phase II-A proof of concept study that will initiate in the second half of this year. We will have the first patient dose second half of this year, and then we expect data mid 2026, and that will be the first cystic fibrosis patient data with an NBD1 stabilizer, again, as an add-on to the standard of care. We will talk about that trial design, I know, later, but that is one of the major milestones we have come up: initiation of the phase II-A, and then data readout mid 2026. The parallel path now of 451 is going into the healthy volunteer dual combination study.
That's a phase I combination study where we will combine 451 with both 2222, SION-2222, which is a TMD1 corrector that we in-licensed from AbbVie, and then our own ICL4 corrector, SION-109, will also be combined with 451, and we'll do a healthy volunteer combination study to evaluate the PK in combination and also the tolerability profile of both in combination. That will also initiate in the second half of this year, and we expect data from that healthy volunteer study in mid 2026 as well. Similar timelines that are rolling out in parallel.
At a high level, can you discuss the rationale for this target and why it has been difficult to optimize historically?
Yeah. Let's talk about the biology of NBD1 first, and then we can talk about the history. What we know, we know what causes CF. It's genetic mutations to the gene, the CFTR gene that impacts the CFTR protein. There are different regions or domains of the CFTR protein. NBD1 is one of the important regions of the protein. What we know is that the number one genetic mutation that causes CF is F508del. That mutation resides within the NBD1 region of the protein. What the mutation does is it causes NBD1 to irreversibly unfold at body temperature. It's creating this instability in the protein, crippling the folding, the trafficking to the cell surface, and just its overall functionality.
What we know is that NBD1, if you can stabilize and correct NBD1, it's the level of correction individually of that regional domain is more significant than any other part of the protein individually. What we've seen preclinically is that if you can stabilize NBD1 individually, the level of correction to the protein is almost equivalent to the triple combination of Trikafta. One mechanism almost equivalent to three. That shows you the power of NBD1. We also know that NBD1 can do a lot of the work in correcting the protein, but we also know to get to fully normal levels of CFTR function, we just need to correct one other part of the protein, which is why that dual combination becomes the strategy.
If we can correct NBD1 plus either ICL4 or TMD1, two other regions, either one of those in combination with NBD1 gives us the potential for wild-type levels of CFTR function, very, very differentiated. What has made it so hard? Why hasn't anybody had this option today, right? It's really because it has been studied. It's not a new target. It has been well known. People have understood the biology and its potential impact, but there have been companies that have tried and have not been able to crack that, mainly because of the very shallow binding pockets that exist around NBD1. It's a very challenging medicinal chemistry exercise, and this goes back to that 15 years of history that I mentioned before with Sionna, leveraging Genzyme and Sanofi to get where we are today. How did we crack this, right?
We used a very structured-based biology approach, X-ray crystallography, knowing exactly where and how our compounds bind, and then building up the compounds almost atom by atom through the activity that we see in the assay and all of our preclinical data. The beauty of NBD1 is everything, all of our preclinical data shows, not just the CFHBE assay, but all of our data shows that NBD1 is doing something fundamentally different to the protein and its correction and the ability to drive incremental benefit for patients. Now we get a chance to move forward with both of these compounds, and we'll start to have CF patient data, you know, in the near term.
Can you walk us through the preclinical data to date that has been presented and how this informs your confidence in these assets?
Yeah. I'll focus on the CFHBE assay because that tends to get a lot of the focus. And for those who don't know, the CFHBE assay is the industry standard in CF. It has been proven to be clinically, it's an in vitro assay, but it has been proven to be highly clinically predictive. And we use the assay in two ways. We use it first as a screening tool to identify which compounds very early have the most activity in the assay. And then we also use it, as I described, in the phase I. We set, it helps us set very specific go, no-go criteria to determine which of our compounds would advance because we set targets for exposure relative to the efficacy we seek to achieve. The assay is a great tool, right? Highly clinically predictive.
What it measures is chloride transport, but that chloride transport then translates to sweat chloride and FEV1. Our preclinical data, specifically with the assay, as I mentioned, demonstrates that NBD1, as an individual agent, has the ability to correct the CFTR protein almost in the same way, equivalence to the triple combination of Trikafta. What our preclinical data also shows is that if we add a second compound, a complementary mechanism like SION-2222 or SION-109, at Emax exposures, we are up into wild-type levels of CFTR function, but even at sub-Emax, we have the ability to add clinically meaningful benefit above the standard of care.
One of the slides we presented last week in our CFHBE was now that we actually have PK and exposure from the phase I, we mapped it back to the HB assay to say, what's the range of possibilities now with the clinical data we have for both 451 and 719? With 719, what you saw was if you anchor to the index of Trikafta being the 1.0 on the scale, what we have the potential with SION-719, when we add it to Trikafta at low doses, we have the potential to be clinically meaningful above Trikafta from anywhere from about 20%-25% improvement all the way up until wild-type levels of CFTR function. We will test that now as we move into the proof of concept study with these lower doses to see what the impact is.
That will be a sweat chloride-based assessment in that proof of concept, but the preclinical data really validates to us that NBD1 has the potential to drive clinically meaningful benefit in combination above the standard of care. You can have it on top of the standard of care, or you can do that in a Sionna proprietary dual combination.
What do you think will be that proof of concept data that really shows that you're able to achieve what you'd like to do either on top of, you know, an existing standard of care or just with regard to your whole construct improving care?
I'll talk about the design of the phase II, but also to start, the goal of the phase II-A is a sweat chloride-based assessment where we will add 719 on top of the standard of care Trikafta, and the goal of that study is to add at least a 10 mmol sweat chloride improvement over Trikafta, right? When we add NBD1 on top of Trikafta, our expectation is that we will drive a 10 mmol sweat chloride improvement versus Trikafta. That's really the goal. That's what we define as clinically meaningful is at least a 10 mmol sweat chloride improvement, which has often translated to about three points of FEV1 improvement.
That is ultimately the clinical endpoint we will go after is FEV1, but the first trial that we are on, the phase II-A in patients, is going to be a sweat chloride-based study specifically. We are confident based on what we have seen preclinically that this will translate. That is what the study will now demonstrate is that we can add this on top and see a sweat chloride benefit for patients. The design of this study, if you step back, it is a very efficient study that we run, II-A crossover study, that we will add 719 on top of Trikafta, first designed to show that sweat chloride improvement that I mentioned, 10 mmol of sweat chloride, but it is also a proof of concept, proof of biology.
It's really a proof of mechanism study that we're running to show that NBD1 is actually differentiated from the components of Trikafta, but also synergistic with, which is why you would see that benefit in sweat chloride. That's what we talk about biologically, right? These compounds work differentiatedly, but they're also synergistic with the components of Trikafta. That will be the second piece. The third is it's our first validation of the CFHBE assay, right? It'll be our opportunity to translate or show the translation from preclinical to phase I and now into CF patients and validate that we can drive the sweat chloride the way we believe we will. That's really the design of this study.
Prove the biology, show it is differentiated but synergistic with Trikafta, demonstrate an improvement in sweat chloride of at least 10 mmol, show the translation of the assay, and then what we also think that will help us, it will in parallel help inform the rest of the study design as we go forward, even for the dual combination. We think with that efficacy data that we have from that phase II, it will help enrollment of the phase II- B dual combination studies. We are really excited about that, and we will have that data again by mid 2026.
Can you walk us through the risk here of assay translation in the context of what you just mentioned?
Yeah. So again, historically, the assay has translated very well, right? It's like, it's very predictive. When you look at our assay, we run it very similar to the way that Vertex does. We're very confident in its profile as well. There's a lot of published literature out there on how to run the assay, and we run it very, very similar. We have a lot of confidence. We have modeled all of the Vertex compounds in our assay and have delivered very similar results to the clinical results that they've published on each of these compounds. So a lot of confidence in the assay. The risk is, you know, this is the first time NBD1, right, will have been being translated. And one of the questions we often get asked is, how do you know that that prediction continues to be linear, right?
That is what it has been historically, this linear prediction of sweat chloride or chloride transport to sweat chloride to FEV1. You know, that is what the future data will show us, does that plot continue to be linear in the future? What we know is that the room for improvement is significant, right? You see where the standard of care, as good a drug as Trikafta is, and we give a lot of credit to what Vertex has done for patients. Again, we know that 2/3 of patients are not at normal CFTR function. That tells you there is more room to go both in terms of sweat chloride, but ultimately also FEV1.
That is what we believe NBD1 is going to unlock, a different level of clinically meaningful benefit for these patients, and we will demonstrate that and then be able to translate back to the assay and see what the impact has been.
Prior to initiating the phase II proof of concept trial for 719 and Trikafta in the second half, you plan to run a drug-drug interaction study. Can you discuss how you plan to disclose these results as well as how it could further de-risk the program?
Yeah. Let me describe why we're doing the DDI study, right? As we mentioned, this will be 719 on top of the standard of care. The reason why we're doing this DDI study is that the components of Trikafta are all sensitive CYP3A substrates, and ivacaftor, well, ivacaftor is a very sensitive CYP3A substrate. They're all CYP3A substrates, ivacaftor being the most sensitive. The DDI study is really, we have a lot of preclinical in vitro data that has shown we have a clear path to add at low doses, we can add 719 or 451 on top of Trikafta and not impact the components of Trikafta because that study, that phase II-A study, people are going to come in on their physician-prescribed Trikafta. We don't want to disturb the dosing. We're not going to change the dosing regimen.
We want to confirm with this DDI study that when we add 719 to the components of Trikafta, they work well together. The DDI study is going to be a midazolam study where we will check versus midazolam, which is also a sensitive CYP3A substrate. It is meant to be a proxy for ivacaftor in this case, right, to demonstrate that we have a clear path. As I mentioned, all of our preclinical data that we have done in these combinations have shown we can add 719 on top of Trikafta and not have an issue. This will be a confirmatory study to do so.
How we will demonstrate or articulate that that's been completed, our plan at this stage is to announce the initiation of the phase II-A proof of concept, not the DDI itself, but by default, by announcing the initiation of the phase II-A, you'll know, and investors and shareholders will know we have successfully completed the DDI, and now we're enrolling and dosing patients in the phase II-A. That's the plan.
You touched on the bar for success here and this 10, you know, millimole improvement in CFTR function that could translate to a meaningful functional improvement on FEV1. Can you just help us understand how you've come to that correlation?
Yeah. There are two ways we look at what is clinically meaningful, right? When you look at historically and the therapies that have been approved, you look at something like Orkambi. Like Orkambi had a very similar profile, 10 mmol sweat chloride, about three points of FEV1, and that was one of the first meaningful benefits beyond ivacaftor that we started to see. That is one barometer that we use that has been demonstrated to be clinically meaningful. When we also engage the community, when we talk to KOLs, when we talk to the Cystic Fibrosis Foundation and others, we have asked this question, right? You have a standard of care today that delivers a certain profile.
If we came up with something new and different that would be meaningful to you, community, what would you look at in terms of something that would excite you and want to use this product? Consistently, the feedback has come back to us at that level. 10 mmol of sweat chloride, three points or more of FEV1, that would be meaningfully different from the standard of care, right? This is always above the standard of care, what its current baseline is, and then you're adding that benefit on top or going above the standard of care. That translates to about a 20%-25% improvement above the standard of care. Our goal is to even be higher than that. That's our minimum. That is the minimum bar we've set, but it's been corroborated by both historical data and also engagement with the community.
How will the phase II data then inform the forward development strategy? Do you see a scenario here where you move forward with 719 as an add-on?
Yeah. That's a good question. If you think about the path that we have, we've laid out 719 as the add-on to standard of care, and then we have 451 as our anchor to the proprietary dual combination. As we have said, our prioritized path is the dual combination. We think ultimately that is the one that is best for patients and ultimately has the highest commercial opportunity as well. This will truly give patients a differentiated opportunity where NBD1 is the anchor and it's only two compounds coming together. From both an efficacy perspective in terms of its potential, but even potentially the tolerability as well, that will have to play out over the development plan, but that is our prioritized path. Your question on the add-on, right?
The phase II-A, as we've said today, 719 moving in that path creates the strategic option for us, right? Today we've said the prioritized path is the dual combination, but we want to be data-driven, so we won't make a decision on the add-on path until we really see that phase II-A data. It is a commercially viable path if you can deliver that level of improvement that we talked about, the 10 mmol that ultimately would translate into FEV1. That is a viable path, but we want to be very focused, be data-driven in terms of how we make these decisions. The reason we really liked the strategy we chose with 719 and 451 going in these two different directions is it does give us the strategic option, but again, we'll be data-driven to help us make that decision.
Your pipeline also includes additional CF modulators and potentiators. Can you speak to your strategy here in terms of pipeline optionality and lifecycle management, recognizing, you know, there's always a need to have backup compounds?
Yeah. If you look at our portfolio, we have four complementary mechanisms that have clinical level data. We have SION-2222, which is a TMD1 corrector, SION-109, an ICL4 corrector. Those are the two that we mentioned are going to be the prioritized complementary compounds that we will combine with 451 in that healthy volunteer dual combination study that will kick off in the second half of this year. We have prioritized those two compounds initially as our complementary mechanisms really because of the profiles that we've seen. Galicaftor or SION-2222, as you may remember, that came from AbbVie. That has phase II data, right, in combination with navocaftor, one of our other drugs, and we have a lot of clinical data on galicaftor, so we have a good sense of the profile of that compound.
When we've done work preclinically, the combination of galicaftor with 719 and 451 has been very powerful, right? It gives us that opportunity to drive that meaningful clinical benefit in dual combination. That's one of the reasons we picked well-defined tolerability profile as well. SION-109, similarly, we now have phase I data. We completed the phase I of 109 earlier this year. It has very positive phase I data both in terms of the exposure targets that we've achieved with 109 and also the tolerability profile combines very nicely with 451, both in the assay and then all of our, you know, the ICL4 and TMD1 correctors, as I said, if you can correct one or other aspect of the protein in addition to NBD1, this is where you have the potential to deliver fully wild-type levels of function.
It is really the profile of both of those compounds individually, what we have seen, and then how they combine nicely with NBD1 is why we prioritize them both. We do have two other compounds, as you mentioned, navocaftor, which is a potentiator, and then we also have 2851, which came from AbbVie as well. Those are the three compounds that came from AbbVie. Those are excellent opportunities for us to think about lifecycle development, right? Later on, we can think about if we need to continue to add a compound to drive even more efficacy. We have those compounds there. Our prioritized focus has been on the dual because we think we can drive that meaningful clinical benefit with just two compounds.
If downstream, we want to continue to elevate the efficacy, if we need to do that, that's what those compounds are there for, is potential lifecycle development in later stages we see how the dual plays out.
How are you thinking about the commercial opportunity here in the context of the various scenarios that could play out?
Yeah. So again, as we talk about the commercial scenario, we've been focused on the dual, right? The dual combination because we said we look at that profile, the potential profile of that compound being differentiated in terms of the mechanism of NBD1 plus one other complementary mechanism, the ability to drive clinically meaningful benefit above the standard of care with just two compounds, and then the tolerability profile, right? That is to be determined as we continue to play this out, but so far, very happy with the tolerability profile we've seen with these compounds individually. We believe that we have the potential to become the new standard of care if we drive all of those benefits that I just talked about. That has been our prioritized path, thinking about how we commercialize that.
The add-on, as we said, when we look at the add-on, this market, like many others, is going to be defined mainly by efficacy, right? If you can drive incremental efficacy, if you can push more patients to normal CFTR function, give them new options that they haven't had today with new mechanisms, there is an opportunity if you're driving the efficacy. When we look at the relative commercialization opportunity of the dual combination versus the add-on, the dual combination provides the most benefits to patients and the potentially most benefits and then also the highest level of commercial opportunity. Again, if we see something data-wise that we think there's a path to advance the add-on, we'll do so based on the data.
is the size of these markets at this point?
Yeah. So it's today, as you probably know, it's an $11 billion market today, right, with one player, and it's growing to $15 billion in the near term, right? Obviously a very sizable market that if you have an opportunity to penetrate that with something that could have a differentiated profile that drives incremental benefit over the standard of care, you can think about what the size of that opportunity is.
The last question here, where do you stand from a cash perspective on your balance sheet and what does, you know, this runway include in terms of drug development?
Yeah. We executed the IPO, as you know, in February of this year. We raised $219 million. That IPO was very helpful for us, gave us tremendous financial flexibility with those proceeds. We have cash runway into 2028. Well beyond these milestones that we talked about today, having the phase II-A data in mid-2026, having the Healthy Volunteer dual combination data in mid-2026, we have runway well beyond that. We have the capital flexibility to execute across this portfolio. With the strategy choice that we made of progressing 719 to the add-on and 451 to the dual combo, it did not change our cash runway. We still have cash runway into 2028 because it was the same development plan. We just chose to push two different compounds in two different directions.
We're well positioned from a cash perspective to execute against the clinical plan and our future prospects as well.
With that, Mike, thank you so much.
Thanks, Salveen. Yeah, pleasure to be here with you. Thanks everyone.