All right. Thanks, everybody. Happy to be here with the Sionna Therapeutics team. With me is Mike Cloonan, CEO, Elena Ridloff, CFO. Always great to see you guys.
You too, Paul.
We'll dig into next steps for NBD1, but maybe I'll turn it over to Mike briefly, just make some quick opening remarks, and maybe Elena, you could chime in too, just on the balance sheet and cash runway as well.
Yeah, great. First, thanks, Paul, and thanks, Stifel, for inviting us. Always great to be with you and to be here at the conference. Just for way of background to kick this off, Sionna is focused on cystic fibrosis. We're focusing on a differentiated target in NBD1, as Paul just said, and our goal and our mission is to provide new meaningful options to people living with CF. We know there's unmet need that exists today. We believe NBD1 has the potential to be disruptive in a very positive way in the CF market. We'll talk today about our plans coming off of the PreciSION data now three months ago, and our plans for the AscenSION CF study, which will be our proof of concept.
Sorry, Paul.
Yeah. Okay. We will be starting our AscenSION CF study in the first quarter of this year. Looking forward to kicking that study off, which will be our two-drug combination of SION-451 and SION-2222. Again, we think we will have the opportunity to drive to a meaningful new option for patients and an opportunity for us to demonstrate the power of NBD1. I will let Elena talk a little bit about our cash runway and some of the plans.
Yeah. We actually announced our third quarter earnings this morning. We ended the third quarter with $250 million in cash, and we have cash runway into the second half of 2029. So we are well-funded today, and as Mike was articulating, we are going to be initiating the first quarter of next year our dual combination study with SION-451 and SION-2222. I am sure we will get more into that.
Yep. Okay, great. Well, maybe to level set, you have had some time now since the phase iiA readout, so obviously the study did not meet your goal. There were some signs of drug activity. Do you want to talk about the different sort of theories you have come up with to explain the result? I have asked you this, and I do not know if it is fair, but people ask you this all the time, how do you sort of rank order them and kind of make sense of what the most likely explanation is here?
Yeah, so I'll start that, Paul. Yes, it's been three months since we announced the PreciSION CF study. Obviously, very disappointed with the results. We felt we had a real opportunity to demonstrate the NBD1 biology and that this combination of SION-719 plus the components of TRIKAFTA would be synergistic and potentially add meaningful benefit to people living with CF. If you step way up, again, that concept of how we initiated that study and why we chose SION-719 and that add-on to TRIKAFTA was we believed there would be synergy. We thought the correction of NBD1, correcting the other part of the protein that TRIKAFTA does not correct, we would have this synergistic four-drug combination that would be beneficial for patients.
When we stepped back and looked at the data, what we think happened was the actual opposite of that there was anti-synergy of adding SION-719 to TRIKAFTA, and we'll talk about that. To your point, Paul, there were three different takeaways that we had when we did our post hoc analysis on the PreciSION dataset. The first was when we did a deep dive into the PK and the sweat chloride results, we saw what we believe was clear evidence of non-adherence. Unfortunately, there were three patients that, in the study, looked like they had been non-adherent to either TRIKAFTA during the washout period when they were only on TRIKAFTA, and there was one patient during the time when they were treated with SION-719 that looked like they were non-adherent for some period of time on SION-719.
That clearly had an impact on the results, and so we ran that dataset by the Cystic Fibrosis Foundation, our clinical advisory board, our primary investigator, because what you don't want to do is cherry-pick, right? We weren't looking to cherry-pick the data out of this and try to save the study. What we really tried to understand is, do we see activity, NBD1 activity in the study? That first assessment of the non-adherence was important because when we did the post hoc and we re-ran the sweat chloride numbers, removing those three subjects, what we saw was a sweat chloride improvement of somewhere between four and nine, depending on whether we used the primary or the secondary analysis.
With that data, and when we looked at the participants who we kept in the study, not removing them, what we saw, the distribution of sweat chloride results and the placebo effect, it looked like target engagement. We could see evidence of NBD1 doing something, although not to the expectation that we had. As everybody remembers, we had set a target of at least 10 is what we expected to have in that study. Even with the removal of those non-adherent patients, we weren't achieving that, but it was still important because we could see that target engagement, that NBD1 was doing something. The second question was, why are we not getting the 10 when we had such a strong belief in what we were going to deliver? That gets to that anti-synergy.
There were actually two other factors when we did the post hoc that we think was the interaction of 719 + TRIKAFTA. The first, which you and I have talked a little bit about, was the PK interaction that we saw, that when we looked at when patients were just on TRIKAFTA during the period of time, there were different points when they're either in the washout period or they're just on TRIKAFTA. We measure their PK, and over that period of time when they were just on TRIKAFTA, their TRIKAFTA exposure levels stayed consistent. But the difference we saw is in the period of time when they were treated with 719 and TRIKAFTA, the TRIKAFTA exposure levels dropped on average 25% to 30% across the components of TRIKAFTA.
We saw this PK interaction, which was very different than what we expected, because as you may remember, we did our DDI study ahead of the PreciSION CF study to confirm we would not have an impact on TRIKAFTA, specifically as it relates to CYP3A4. That's the DDI we were looking at prior to the study. We do not believe this PK interaction is CYP3A4. We think there's something else going on with this four-drug combination that's hard to explain with the data that we have. And the only way we could understand it is if you did more work and more studying of this four-drug combination, which we're not going to do.
But that was truly a confounder and hard to quantify what impact that could have on sweat chloride, but not unreasonable to think that if TRIKAFTA's levels are coming down when treated with 719, could that be enabling sweat chloride to drift back up and in some ways mask the benefit of NBD1?
Yeah. And you guys have tried to dig into whether there's any withdrawal data or anything like that. We can try to quantify it theoretically, but there's really nothing tangible out there?
It's so hard. We really looked at this, right? Because it would have been great to be able to say, "We can observe it, we see the difference, we can measure it.
Right.
If we could quantify it and say it had a sweat chloride impact of X, then that would have been-
Right
beneficial for us to be able to say, "Okay, take out the non-adherence patients. You've got this PK interaction, and all of a sudden, does that start to look like what we would expect?" We just don't have enough data. With a small patient dataset and sparse PK, and the difference in the PK across each component of TRIKAFTA, the elexacaftor, tezacaftor, and ivacaftor was different. It wasn't the same across every patient and across every aspect of TRIKAFTA. Very complex puzzle to solve, as much as we tried. But that was an important finding for us. Then the third, which was also part of this anti-synergy that we've talked about, was more of a biological interaction of SION-719 in combination with ivacaftor, the potentiator that exists within the three-drug combination.
Really what that looked to us, you could see going into the study, we believed that synergy was going to be beneficial in combining NBD1 with all of the components of TRIKAFTA. But what we think actually happened was there was a biological interaction that we think muted the benefit of NBD1. In reality, what you see is we're putting so much open channel protein to the cell surface when we stabilize NBD1, and the role of the potentiator is to open that channel and allow the chloride ions to pass through. What we think is when you put that much protein to the cell surface in the presence of a potentiator, it could be creating a non-physiologic or dysregulated state for the cell, because normal CFTR function does not require a potentiator.
We think there's a point in time when maybe a potentiator is helpful, but when too much protein hits the cell surface, it may become counterproductive, and we think that was also a potential blunting of NBD1's impact. That's a hypothesis, right, that we've dug deeply into, and we worked with the biologists at the Cystic Fibrosis Foundation as well to pressure test this. We think it's a valid hypothesis, and again, just really speaks to this four-drug combination that we thought was going to play nicely together on many dimensions was anti-synergistic, both from a PK perspective and a biological interaction perspective.
Looking ahead, you're going to look at a combo that doesn't have a potentiator. Part of the goal of phase IIA was to sort of reaffirm that you're right on the assay, to figure out the dose range. Let's just say that the phase IIA, look, it was negative, but let's say even it was just neutral, right? Because it's kind of hard to interpret all this stuff. How do you then go about figuring out the right dose range for the next study?
Yeah, so we still have to rely on the assay, right? You come out of that study, we had an expectation of what we thought PreciSION was going to show us. It didn't deliver that expectation, and when we dug in, as all of those three measures I said before, we can see that coming out of that dataset, when we look at, we need to change our evaluation of the assay specifically when the potentiator is on board, right? Because of this biological interaction. That's our hypothesis. But when we look at the dual combination, you were sort of referencing this, in all of our preclinical data, we don't see the same behavior when you take the potentiator out of the mix, right? The shape of the CFTR function and the current looks very much like wild type.
When you have our two-drug combination of SION-451, the NBD1 stabilizer + SION-2222, which is a TMD1 corrector, when you put those two things together, they look very similar to wild type CFTR function in the HBE assay. We still need to rely. The assay is an important tool still. We learn from the PreciSION CF dataset, we learn from that four-drug combination, but we still leverage it to help us set what we think the right dose and range is that enables us to deliver at least an equivalent two-drug combination to the three-drug combination of TRIKAFTA, and the potential to deliver even more than that.
Yeah.
Clinically meaningful benefit beyond that. The assay is still an important tool for us. We just have to continue to look at how we leverage it, and the goal really is when we look at our dose ranges, we have enough belief beyond even, right, the single prediction of what those would look like, that we can go even higher than what the assay predicts.
Yep. Okay, great. Maybe now looking ahead, do you want to talk about the design of the next study? And obviously the readout is a ways away, but I think the natural question when we saw the design was, okay, cool, clever study. What's a win?
Yeah.
So maybe talk about-
I'll let Elena talk that one.
your thoughts there.
Yeah. Our next study will be a phase II proof of concept study looking at SION-451 and SION-2222. This is our novel combination of an NBD1 and a TMD1 corrector. It is going to be an open-label study. Patients will come from TRIKAFTA, homozygous patients, and they will switch to SION-451, SION-2222, and that will be a 28-day study, and the primary activity endpoint will be sweat chloride. We asked what good would look like, and as we have engaged with the community for quite some time now, there is a real desire for alternatives to TRIKAFTA and ALYFTREK. Both those combinations have their own tolerability challenges, and we heard it again at the NACFC meeting this year, just how much the community really desires alternative options.
Equivalent is certainly a very exciting profile in this $13 billion and growing market, and we have the potential to deliver that and even potentially something superior to TRIKAFTA.
Yeah. Okay. Makes sense. Do you have any sense of the size of the study and maybe the types of patients that would enroll in a trial like this?
We will provide more details on the size in the first quarter, when we start to get the study up and going. We are still finalizing the protocol. As far as the type of patients, we are going to be targeting similar types of patients that enrolled into PreciSION. So, patients who are not yet at normal from a sweat chloride perspective.
But have responded some.
But have responded some, and we still believe have that dynamic range to show potential improvement.
And maybe one interesting add to that, Paul, is when you think about PreciSION, it was what Elena said. We wanted people to have a typical response to TRIKAFTA, so this is not going to be patients who are already at normal, below 30. We did not want folks to be so high in their sweat chloride that maybe there was something going on specifically with them, that they were a non-responder in some shape or form. So, we will have entry criteria on sweat chloride again. But one interesting feedback that we have heard is that with PreciSION, we designed that study thinking it was going to be the most patient-friendly study because they would not have to come off TRIKAFTA, right?
Right.
We thought that would be easy to enroll. People wouldn't have to come off the standard of care. But in reality, we weren't giving them a new option per se, right?
Right.
We were kind of boosting them, if you will.
Yeah
By adding NBD1, but they still had to stay on their TRIKAFTA. With the dual combination, there's been some interesting feedback, like, "Now you're actually giving us a different option." This could be things like folks that may be having some tolerability issues, right, whether that's the CNS side effects or it's the liver, and also maybe not having the level of reduction in sweat chloride that they were hoping for. So, it may open up a different set of patients for us that we weren't able to get at through PreciSION because they had to stay on TRIKAFTA.
Yeah. Okay. It sounds like you're fairly confident that you'll be able to enroll this study and that there's a good amount of patients out there that are pretty willing to switch from their TRIKAFTA to try something else. What gives you that confidence? What work have you done on the feasibility of it?
Yeah. I think it's the sites themselves and it's the community feedback. Elena was saying, at NACFC, we were just there a few weeks ago, and the embrace that we received from the community at that conference was very impressive for us, to see how much they wanted us to continue on this path. We need new options. The unmet need continues to be high. They want somebody new to work with in the space. And we have all the site engagement that we've had, tremendous response, right, from the sites, and even post-PreciSION, right? It didn't skip a beat. We were doing that in parallel as we were waiting for the data on PreciSION. And with that data, we saw in some ways even more engagement, that how powerful they see this dual combination option being for them. And so, we've done the feasibility.
We know how many patients exist at the different sites and what we think we need to have from an enrollment perspective at each site. And as Elena said, we'll give more detail around the number of sites, the number of patients. At this stage, we know it's still going to be a small study, right? This is still going to be a proof of concept of the dual combination. It will be a little bit bigger than PreciSION. How much bigger? That's being finalized, and when we have all those details, we're going to be happy to share them in that first quarter.
Yeah. Okay. Makes sense. Maybe thinking ahead, right, if these data are positive, how are you guys thinking about the best path to get to market? Do you feel like it ultimately has to be a head-to-head study, and what could that sort of look like, and what could that kind of require from a resources perspective?
Yeah. The next step after this study would be a phase IIB dose-ranging study-
Okay
and then a phase III. Once we start to see the profile from, as far as where we are sitting in efficacy range, then that will help us determine the phase III design, whether that is non-inferiority or superiority. If you look at the ALYFTREK phase III, that is a very clear example-
That is a good analog, you think?
of an analog for a non-inferiority, yeah.
Yeah. I mean, if you go non-inferiority, as you know, there is a sort of counterintuitive, you have a bigger study, right, for non-inferiority.
Right.
And so, it does still typically allow you the ability to look for superiority-
Right
if you design the study for non-inferiority. So, there is a benefit of that study. It almost gives you two shots, right, to hit non-inferiority, and then if you hit superiority, you can have that as well. The data is going to drive us, ultimately, in terms of the trial design. If we see the ability to have meaningful benefit beyond the standard of care, a superior study is in play, but we want to see how the proof of concept plays out. We will see the dose-ranging study, and then that will enable the phase III design.
Yeah. Okay. So maybe, I guess, taking a step back, right, what do you think is most misunderstood about the story at this point, as people have kind of sifted through the phase iiA results and try to think about what is next?
Yeah. I think, for me, there is a couple of things. I think the first is that the dual combination was always our prioritized path. You know this. You have been following us for a long time now, and from the very beginning, our goal had always been to create a positive level of disruption and shift the paradigm in CF with the power of NBD1. So our goal had always been, we will develop a two-drug combination that we think has the ability to be at least the same as the three-drug combination because of the power of NBD1, and potentially even better than that, and hit that superiority marker. So, that strategy has not changed, right? PreciSION was designed, and we ran that study to help enable that strategy. It did not because of those results, but it did not fundamentally change the strategy.
I think that's important when we look at the potential of what we have to do. All of the key strategic and value creation opportunities that we have are the same as prior to PreciSION. We understand, right, what happens when you have a negative study and you've got to prove it to people, right, that this wasn't in some ways an indictment of NBD1. Fundamentally, when we've taken the time to evaluate that post hoc data, we can compartmentalize PreciSION and say, "Okay, this is a derivative of the four-drug study. This is a result of combining SION-719 with TRIKAFTA." We had an expectation going in. It played out very, very differently, and when we pull back and we look at this, there was anti-synergy. This worked against each other, so it does not refute the NBD1 hypothesis.
We did that work so that we could feel confident moving forward with the dual combinations. I think it's just reiterating for folks, all of the beliefs going into PreciSION still exist with the power of NBD1. We have to prove that, right? We have to prove that with the next study. I'd say the second is the amount of robust data that both we have and then the public that exists around NBD1, and how important a target this is. It has been known for a long time how differentiated and important NBD1 could be in the correction of the CFTR protein. To this point, as you know, it has been considered undruggable for many, many years.
Yeah.
We're so far ahead of where we were several years ago of refuting that hypothesis, and now again, we're moving into a phase II proof of concept study with the dual, so we're very much looking forward to kicking that study off and providing that data. That's going to be the ultimate new test for us to demonstrate what we continue to believe is the power of NBD1 is very meaningful, and we think this is going to play a really important role in the future of CF treatment.
Yep. Okay. Very good. Anything else you guys would like to add before we wrap up?
Well, no, I think we're in a good place right now, Paul. It's always tough coming off of a failed study like PreciSION, where we had so much hope going into it and really had conviction of what we thought we were going to see. But it's been a period of time, and as you know, biotech is a tough space, and you've got to learn from that, and there are some things I think we did learn from that study that were different than what we had going in. One of those might actually be, you might not need a potentiator.
Right.
If you go way back, that was one of the questions we had when we first initiated.
I remember the company. Yeah, I remember.
We talked about this, right?
Yeah.
Because every approved combination that exists today has a potentiator in it, there was always that question, do you need a potentiator to drive the benefit? Our hypothesis was, we probably don't need a potentiator, but we didn't think it would hurt, right, to have a potentiator. That may not be what we saw in PreciSION. That hypothesis, again, around the NBD1 working in contrast with the potentiator might have been a tough way to learn what we had a hypothesis around, which you might not need a potentiator. Again, that's why I come back to that two-drug combination anchored by NBD1 has always been our strategy without a potentiator. This is going to be the more pure way to test the NBD1 hypothesis with the dual. Again, we've got to learn from PreciSION.
We're baking those learnings into the design as we've had to leverage some of the key things that we found, both in terms of adherence, how do we not have that happen again in the next study? How do we reduce some of the variability we saw in sweat chloride? All of that is being baked into the study design. Again, that's what you have to do as leaders of an organization, is learn from what-
Right
went different than you expected, and then set yourself up for success going forward. We look forward to kicking that off in the first quarter.
All right. Best of luck. Thank you both.
Thank you, Paul.
Good seeing you.
Thank you.