Sionna Therapeutics 3rd Annual Guggenheim Healthcare Innovation Conference

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 Cloonan, the CEO. As Yatin said, I'll just give you the quick background on the company, and then we can launch into the Q&A. So, just by way of background, as you probably know, Sionna 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, excuse me, 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 reflect 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 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 NBD1.

We still have a very strong belief in the differentiation and the opportunity that we have ahead of us with NBD1, and specifically, our focus going forward on a two-drug or a dual combination moving forward with SION-451, our NBD1 asset, plus SION-2222, our TMD1 asset, in a two-drug combination that will kick off its proof of concept in the first quarter of next year. 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 II proof of concept study with our dual combination kicking off in the first quarter that we think will put us in a very good position. 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 SION-719, our NBD1 stabilizer, we would see significant synergy in combination with Trikafta. 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 SION-719 with Trikafta 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. 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. That's our approach going forward. We'll get into more details, I'm sure, today. Again, disappointed with the results of PreciSION, learned a lot from it, excited about the next chapter for Sionna in starting the two-drug combination of SION-451 and 2222 next quarter.

Yeah, I can start, and I'll let Charlotte chime in on this too. If you look at one of the things you're referencing, Yatin, 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 Trikafta. Then there was a period of time when they were Trikafta plus SION-719. And what we observed in the study was that when patients are on SION-719 and Trikafta, the exposure of Trikafta in that four-drug combination was on average 25%-30% less than when they were just on Trikafta alone.

There was some interaction happening with these four drugs that reduced the exposure of Trikafta, and that was something very different than what we expected, and that gets back to that anti-synergy comment that I mentioned before of what we expected. 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 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. We knew, of course, going into this that there was one obvious potential PK interaction, based on the CYP3A4 pathway. And so we had done a midazolam DDI study ahead of time to mitigate that particular component of it. 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 a helpful one.

Exactly what it was, looks like it was complex and somewhat 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 SION-719 to. One of the reasons why we're just simply not going to be going forward with this four-drug combination.

Yes. So again, there was this PK interaction that we observed that didn't help, and it was complex. Just to put a pin on that, we have put SION-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 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.