GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - SIONNA THERAPEUTICS INC

Annual Guggenheim Healthcare Innovation Conference. My name is Yatin Suneja, one of the senior biotech analysts here at the firm. It is my pleasure to welcome our next presenting company, Siona. We have a few executives here from Siona, we have Mike Clonin, who is the chief executive officer with us. We have Charlotte McKee, she is the Chief Medical Officer, and we also have the Chief Financial Officer, Elena Ridloff here. A lot to discuss. Mike, why don't you make some opening comments? It was a busy year for you guys. You have the update in August. Maybe recap that a little bit to us, and then just talk about some of the milestones that we should be focusing on, and then we'll go into some of our Q&A. That sounds good. Well, first, Yatin, thank you for inviting us, as always. Great to be here with you and with Guggenheim, and great to see everybody in the room. So I'm Mike Loonan, the CEO. As Yatin said, I'll just give you the quick background on the company, and then мы can launch into the Q&As. So just by way of background, as you probably know, Siona is focused on cystic fibrosis. We are targeting a very different, unique mechanism in NBD1 that we think could unlock differential efficacy and new potential in CF and potentially drive patients to fully normal CFTR function. That has always been our focus. The history behind NBd1 is very strong in terms of its potential. and we believe with our portfolio of options, we can deliver something very unique and meaningful for patients going forward. When we reflected back, as Yatin said, over the course of this year, we had our precision CF readout back in August, which was very disappointing. We were expecting a positive study there. We had a lot of information going in that conviction around NBD1 and its combination with Trikafta. So that was an add-on study that we launched and the data was was not positive. But we dug into that over the period of time and came out with our post-hoc analysis that we believe we have strong rationale and understanding of what happened in precision that did not change our belief and conviction in NBD-1. We still have a very strong belief in the differentiation and the opportunity that we have ahead of us with NBd-1, and specifically our focus going forward on a two-drug or a dual combination moving forward with 451 our NBD1 asset, plus Scion 2222, our TMD1 asset, in a two-drug combination that will kick off its proof of concept in the first quarter of next year. So lots of learnings from Precision that I'm sure we'll get into a little bit today in terms of why the study didn't deliver the results that we expected, and then also leveraging those learnings as we design this next Phase 2 proof of concepts study with our dual combination kicking off in the third quarter. in the second quarter that we think will put us in a very good position. And as I said, the fundamental hypothesis hasn't changed around NBD1. What we believe at a high level that happened in precision was going into that study, our hypothesis was that by adding 719, our NBd1 stabilizer, we would see significant synergy in combination with Trikafta. And when we got the results, what we actually saw was what we thought was anti-synergy. There were things happening both at a PK level and a biological level when we combined 719 with Triikafta that was very different than what we expected going in. But we've learned from that. We've assessed that. And again, we believe it's going to be very different with our dual combination going forward. And the NBD1 hypothesis remains very much intact. And so if we can do that, if we can deliver this next study and get back on track in terms of the belief and conviction around NBd1, that was always our prioritized path. If you remember back in the early days when we were talking with you, Yatin, that two-drug dual combination strategy was always our preferred strategy, that we could compete directly with Vertex and their triple combination drugs, but we had NBD1. That was very unique and differentiated, and what we think we can do with two drugs can be at least as good, if not better, than those three drug combinations. So that's our approach going forward. We'll get into more details, I'm sure, today. So again, disappointed with the results of precision, learned a lot from it, excited about the next chapter for Ciona and starting the two drug combination of 451 and 2222 next quarter. Well, thank you, Mike, for that. So I'm going to spend time on the dual combo, but we'll go there first, maybe, you know, talk about some of the learnings in a little bit more detail, right, and why that should not be, or hopefully we have sort of addressed that. So why, like, what was the reason why you were seeing some lower exposure with Trikafta, and what gives you confidence that, you know, you will not have sort of the same interaction with 451? Yeah, I can start, and I'll let Charlotte chime in on this, too. So if you look at one of the things you're referencing, Yacht, and one of the learnings that we had in the precision study was we had periods of time in precision when patients were just on Trikafta. And we measure their PK, and we look at what it looks like just on Trikahta, then there was a period of time when they were Trikapta plus 719. And what we observed in the study was that when patients are on 719 and Trikaarta, the exposure of Trikaorta in that four-drug combination was, on average 25% to 30% less than when they were just on Trikafta alone. So there was some interaction happening with these four drugs that reduced the exposure of Trikahta. And that was something very different than what we expected. And it gets back to that anti-synergy comment that I mentioned before of what we expect. I'll let Charlotte maybe talk a little bit why that was and how that was different from the DDI study that we did before launching Precision. Because, you know, some people are leaping to the, is this CYP3A4? What is this interaction that's happening? But I'll let Charlotte talk through that. Yeah. So we knew, of course, going into this, that there was one obvious potential PK interaction, you know? Based on the CYIP3A3 pathway. And so we had done a midazolam DDI study ahead of time to mitigate that particular component of it. So going in, we didn't expect and we didn t see that to be a massive driver of potential interaction. The bottom line is there, we believe, and based on the evidence, there was some complex, frankly, it might take us a PhD thesis to try to tease out exactly what happened and why. But there was a complex interaction that we could have only seen when we did what we did, which was put the four drugs together in human beings. And it wasn't a positive one. It wasn't an helpful one. Exactly what it was, it looks like it was complex and somewhat, you know, maybe different even patient to patient. But it didn't help us. And it didn't provide what we were expecting, which was a stable Trikafta baseline to then add 7192. So one of the reasons why we're just simply not going to be going forward with this four-drug combination. Got it. And then maybe one more point. I think you've talked about some pre-stimulation activity that was happening with 719. How should we think about 451 in that context? Yes. So, again, there was this PK interaction that we observed that didn't help, and it was complex. One of the, just to put a pin on that, we have put 451 and 222 together in combination and looked at their PK in Healthy Volunteers, so we know going forward exactly how those two are behaving and we're not, you know, we don't see anything like what we saw with the four-drug combination. So that, from the PK perspective, we're in a very good position going forward. What you've referenced is then the third category of what looks to us like anti-synergy, and this is at the level of the biology. This is a hypothesis. And, you know, the bottom line here, too, is that what we believe we're seeing as far as anti-synergy with the four-drug combination, specifically when we put our MBD1 stabilizers together with a potentiator and stent open all those normal channels, We don't see that same behavior biologically with the two-drug combination that does not have a potentiator on board. So all of these things, if the hypothesis is correct, not something we would expect to see with the two-Drug combination. Got it. So let's talk about the dual-combo study that you're thinking. Number one, remind us what the key difference is between 451 and 719. I know from day one, I think you picked 719 for Trikafta, but 451 for your double combo. What is the difference? Are the scaffolds same or different? Yeah, so I'll start with that. So, yes, they're very similar. They're more similar than they are different. They're from the same scaffold. They have, you know, they'RE differentiated molecules, and they have some slightly different potency. And so if you'll remember from before when we were first differentiating them into the two studies, we chose 719 to go into the add-on study because of its slightly higher potency, because we were then combining with the four drugs altogether. 451 behaves very similarly, but we achieved higher exposures in the phase one healthy volunteer studies. And because we're just combining 451 with our own single, you know, 2222 Gallicafter, we didn't, that potency wasn't such an important piece. And so biologically, same target, same scaffold, but the 451-2222 dual combination actually together puts us in a very positive, you know, a place in our HBE predictions where we would be at least as good as the standard of care, very likely better, and potentially up into wild type range of CFTR function. Got it. So when you announced the precision data, I think at a similar time you announced a dual combo data. So it was mostly overlooked, right, at that time point. So maybe reframe for us, why did you pick TMD1 or ICL4? Yes. So one of the many advantages, and we know this from the biology of the MBD1 stabilizers, is if you combine, if we combine in our preclinical data, in our preclinical assays, if we combined one of our MBD2 stabilizers like 451 with just one other complementary corrector or interface domain stabilizer, either a TMD1-focused corrector or an ICL4-focused corrector that we, it looks like we can drive equivalent or better CFTR function to the triple combinations. And so that is the power of NBD1. So just one other interface domain or complementary corrector, either a TMD-1 corrector like Gallicafter or an ICL-4 corrector like our own Cyan-109. And so we had the luxury of being able to look at both of those dual combinations in the Healthy Volunteers, and just because of how they played together and where their exposures were, the 451-2222 combination put us higher on the map in terms of predictions and played very nicely together. And so that's the combination that we'll be taking forward. Yes, we had the beauty, as Charlotte said, we could be agnostic to ICL4 or Team New One. It was really a compound selection, which one of those compounds between 2222 and 109 performed the best. For both of them, they achieved our PK profiles that we had set ahead. So we did have this luxury of being able to choose the best one, and the 451-2222 gives us the ability to get the highest in terms of the efficacy, as Sherald said. And then for 2222, the TMD1, you're going with the QD, so once a day, right? Do you have the coverage? How does that data look like relative to the BID? Yes. The nice thing about that once-a-day profile was, one, as you may remember, You know, Gallicafter was, you know, developed by AbbVie and even back to the Galapagos days. So there's a tremendous amount or there's lot of data in both Healthy Volunteers and people with CF with Gallicaftor. It's all been once a day. And so that, you now, we have a whole profile. And so we had actually tested and pushed the envelope looking to see whether a twice-a-day profile might actually be better from a PK perspective, but it turns out we don't need it. And that was more than we needed in terms of 2-2-2. So we were able to, you know, to optimize that once-a-day profile, and we can harken back to a lot of, you know, PK and other data with 2222 once a day as well, which is very helpful. The 451 would be BID? Correct. Okay. Now, in terms of the ascension CF study, maybe give us a little bit more color, the size, scope, type of type of patient, baseline sweat chloride, all of that? For Precision CF. Ascension. Oh, Ascention CF. Yes. So we're not, you know, some of those details we're still finalizing. It will be a proof of concept phase two study. As you've heard, it will be open label. And we're going to be able to leverage and learn a lot of the things we learned from Precision CS. So we'll be paying a lot of attention to patient adherence and making sure that the sites and the patients are all on the same page with respect to dosing. It will be in some ways a much simpler study, 28 days of dosing, the proposal is patients will come in stable on their Trikaft and then simply switch to our dual combination for 28 days. So simple, straightforward. We're in deep conversations with the sites and the CF Foundation in terms of the design and how the study is configured. But it looks like we'll be able to address the question. And when you say the simple switch is basically everybody comes, stabilize, and try CAFTA, there is no holiday. Correct. So you just switch. Correct, and they're homozygous as well. Homozygious patients. Yep. And then also in this study, you should, because there is maybe there is some Trikafta on board for a couple days, but you should not have that, it's not gonna be on board in general, right? So you don't have the same issue that- It's a 28-day study, right. So by the end of the 28 days, the effect will be from our dual combination. From all, yeah. And then the other point was that because you won't have the exposure issue that was there. That's correct. Right. No inter... We're not there... No interaction. There will be no interaction by, you know, well before the 28 days Trikafta should be long. Got it. And what the goal is here, like, I mean, 28 days, I'm in again, should we focus only on sweat chloride or that's what we'll be focusing on? Once again, for this proof of concept, primary activity readout will be sweat chloride. Okay. What is the timing? And this is just a U.S. study or outside U.N. study? So focusing on the U.C. and the timing we'll initiate in Q1. We haven't given guidance yet on when we expect the study to finish and top-line data. We typically like to start the study, evaluate how the enrollment is going, and then we can give clearer guidance on when мы expect the study to, to finish. But as Charlotte said, it'll be a smaller study, most likely bigger than precision. and we'll give more details once it's been finalized. We're doing that now. The goal is to wrap all of the protocol up and get all the sites ready to go and then launch the study in Q1 and then we can provide more details on the specifics of study numbers, et cetera. Got it. And how does the regulatory part look like? So after this study, you probably do a phase two study and then go into pivotal and then how should we think about the arm of that pivotal study? Yeah, so very high level, you know, because obviously, so the next step, if after this proof of concept, would be dose ranging. And, you know, we've said this before, so our expectation would be a dual combination dose ranging study. And then the step after that would be, as you said, a pivotal, you know, our expectation will be a phase three study, which we expect would look pretty straightforward. You know, we'd be looking to test, you know, the efficacy and safety of, ideally, a single dose of the dual combination, and we'd obviously be talking, speaking deeply with regulators, you know ahead of time, and making, you now, looking at exactly what those plans would be, but conceptually quite simple. Got it. And then we'd also expand from homozygous to heterozygious, right? The goal is to have F508 del patient population at launch, that that would be in the label, So that would be contemplated as part of the dose ranging in the phase three as well. But most likely a non-inferiority type study or you go placebo? It's TBD, right? So again, you can do a non inferiority study, right, at the end of the day, but it's going to come down to what does this data show us? As Charlotte referenced earlier, our data still shows the potential to get to superiority. And if you think about how we design the study and how we think about the potential, we think about it in two ways, Yacht. And we think About our target product profile is still superiority. Can we drive clinically meaningful benefit beyond the standard of care with our two-drug combination? That is our TPP. The minimum product profile is equivalency. That has always been the case for us. And what we consistently hear from the community is that they want new options, differentiated options. And if you can do something that's even equivalent, that would be very meaningful to them. That's why it's our MPP. But we still believe there's the possibility to achieve the target product profile of superiority. Got it. And then with regard to your assay, any modification, any new learnings applied to that assay? Yeah, I would say, you know, one of the things, we've talked a lot, and you mentioned this whole, you know, some of the details in the assay that we saw specifically with that four-drug combination, and specifically when there is a potentiator on board, not to get too deep into it, but when NBD1 stabilizers drive in our hands and in others, drive an unprecedented level of normal CFTR function to the cell surface. That's one of their massive differentiators and advantages. and our hypothesis is that in the presence then of a potentiator, that may be too much of a good thing. And so that is something that we have. It's not a modification in the assay, but it's a potential post hoc modification in how we view the assays. That was another reason why it was so important to us to dive as deeply as possible into the precision CF data to see if we saw evidence of NBD1 biology in that study, and we did. So the core of our assays remains very much intact to us. How we view looking at things with a potentiator, for example, and how we view the regulation of the CFTR channel has been informed by the precision CF. Got it. Any view on the competition? I think Vertex sort of is talking about 4.0 now version. Just curious to hear from you, how do you think that sort of competitive dynamic changing? Yeah, we do watch, obviously, the competitive landscape very closely. I mean, with Vertex, they just announced their 828 program, right, which was part of their 3.0, I think version 3.5, their pipeline. And from the results of that data, it looks very similar to AlephTrek, right? That was in heterozygous patients. I think their range, depending on how you look at the measurement, was between six and a half and nine. Alephtrek was an eight, right, in that same patient population. So again, it looks very Aleph-Trek-like. So when we look at that data, it doesn't fundamentally change what we think the opportunity is for us, because it's similar to Alephrek. We continue to believe our two-drug combination offers something very different and meaningful because of the power of NBD1, potentially being able to deliver meaningful benefit beyond the standard of care. So that doesn't change. They're 4.0. They haven't talked yet about specifically what that is. We'll continue to monitor that. We believe we are the leader in NBD1. We've got a strong portfolio of assets there. We're in phase two now with our dual accommodation. So we'll continue to invest in NBT1. And we think it's such an important part of the story of the future of CF that it's going to be part of The Armamentarium in CF. And, and we believe we're the ones that are going to be able to do that. Got it. Very good. Maybe then final question on the financials. How's the balance sheet, the run rate? Yeah, so we ended the second quarter with $268 million in cash. We're in a strong cash position. We've really prioritized our clinical investments in the dual combination going forward and resized the company to support that. So we have extended our cash runway into the second half of 2029. So, we're in an extremely strong cash situation. in a strong cash position to execute on the study and take us well past the results. Very good. Very good, thank you so much. Thanks, John. Good to see you. Thanks, everyone. Thank you.