Conference Transcript - SION 2026-06-03

AJ, Analyst — Jefferies

Hi, everyone. My name is AJ. Welcome to the Jeffreys Healthcare Conference. It is my pleasure to introduce Mike Clunin of Siona Therapeutics.

Mike Clunan, CEO

Thanks, AJ. Good afternoon, everyone. It's a pleasure to be with you. Nice to see you all today. Thank you for joining. And also thank you, AJ and Jeffreys, for the invitation to present. These are our disclosures. We will be making forward-looking statements. Actual results may differ. Siona is on a mission to transform the treatment paradigm in cystic fibrosis by leveraging our unique and differentiated NBD1 stabilizers in combinations that have the potential to deliver clinically meaningful benefit for people living with CF. And although Siona has been in existence for six and a half years, we have a very rich history. We spun out of Sanofi back in late 2019, but the science behind our programs originated at Genzyme over 15 years ago. And it's because of that rich history, that experience and knowledge that we have against this very important target, NBD1, that puts us in this unique position to potentially positively disrupt the CF market. There are four key parts of the Siona story. The first is, despite the significant advancements that have been made in cystic fibrosis over the last several years, the unmet need continues to be high in CF. And you can define that by quality of life, life expectancy, or the number of patients that get to normal CFTR protein function. And we know that today, even for the patients that are on the standard of care, only one-third of them get to normal CFTR function. And that should ultimately be the goal, get as many patients to normal CFTR function as possible, so you know there's two-thirds of patients that have that unmet need, and that's really where the opportunity is for Siona. If we can develop new options for patients that drive more of them to normal CFTR function, not only could that potentially be transformational for those patients, it's also a very significant commercial opportunity. This market is a $12 to $13 billion market today that's growing to over $15 billion by the end of this decade. The second key part of our story is NBD1, the biology that we're going to get into on the next slide. It is not a new target. It's a target that has been well studied and well understood. But for many, many years, it was considered undruggable. But NBD1 really is the key to fully correcting the CFTR protein. And we know that none of the approved CFTR modulators directly stabilize NBD1. So it is clearly unique and differentiated from the current standard of care. Third, we're very fortunate to leverage the gold standard in vitro CFHPE assay. The assay has been validated clinically because it has demonstrated a high degree of predictability in clinical trials from the predictions of the assay. We're very confident in our assay's predictive power, and we'll talk more about that in a future slide in the presentation. And then lastly, as much as NBD1 is such a core part of our story, we're also investing in complementary mechanisms that support our combination strategy and have an opportunity for us to deliver something very differentiated for people living with CF that could drive meaningful clinical benefit in the future. Now, let's talk about the biology of NBD1 and why it is so important. We know what causes CF. It's genetic mutations to the CFTR gene that impact the CFTR protein. The number one genetic mutation that causes CF is called F508-DEL, and approximately 90% of patients have a form of the F508-DEL 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 the protein, it's crippling the folding, its ability to traffic to the cell surface, and then its overall functionality is impaired. The current standard of care is a triple combination that is correcting around NBD1. It's partially correcting the protein, not directly stabilizing NBD1. And what we know from all of our preclinical data is that if you can stabilize and correct NBD1, you will create the highest level of correction to the protein, more so than any other aspect as an individual compound. We also know that the monotherapy NBD-1 in our preclinical models creates a similar level of correction to the triple combination of the standard of care. So the single compound, nearly equivalent to the triple combination. So this is why there's a lot of hope now with a new target, a new mechanism that could potentially drive more patients to normal CFTR function. The way that we can do that is by combining NBD1 with just one other compound, correcting one other part of the protein, either ICL4 or TMD1, in combination with NBD1, could drive patients to normal CFTR function, which is why the dual combination strategy that we'll talk about is so important to the Siona approach. Let's talk about our pipeline. So we have two different NBD1 stabilizers that are being developed in two different ways. Scion 719 is currently in a proof-of-concept study where we're testing 719 as an add-on to the standard of care. That proof-of-concept study called Precision CF is now fully enrolled, and we expect to have that data in the summer of 2026. I'll talk more about the study design in a few slides. We also have our second NBD1 stabilizer, Scion 451, which is the anchor to our dual combination strategy. That is currently in a phase one healthy volunteer study where we're looking at two different two drug combinations with 451. We're looking at 451 in combination with Gallicafter, where Scion 2222, and we're also looking at 451 in combination with Scion 109. The goal of that study is to look at the PK and the safety and tolerability of the two drug combinations we'll have that data in the summer of 2026 and the plan is to select the best dual combination that we would progress in development from there so we've made a ton of progress in 2026 that sets us up for this very exciting time in the summer where we're expecting the data from the precision CF study the proof of concept study with 719 as an add-on to the standard of care we also will have the 451 dual combination data to help us select which accommodation goes forward, and we are in a very good financial position where we have 290 million in cash at the end of Q1 that gives us runway into 2028, well beyond those summer 2026 milestones. Now let's talk a little about 719 and 451. As I said, they're both advancing as you saw on the pipeline slide, but they're advancing in two different directions and two different ways to support the clinical development strategy. On the left-hand part of the slide you see the PK curves from our healthy volunteer study of the monotherapy 719. And if you look here, I want to orient you to the PK curve because prior to doing the phase one with 719, we leveraged our CFHBE model to determine very specific concentration targets that we needed to achieve in the phase one that would enable us to drive clinically meaningful benefit in two different ways. One is if we added 719 on top of the standard of care. The second would be if 719 was part of a dual combination with our other complementary mechanisms. If you look at the PK curve and you look at those teal hash lines, you can see the lower hash line is the target that we had set to deliver clinically meaningful benefit as an add-on when added to the standard of care. The higher teal line is when we have 719 as part of a dual combination. Simply stated, the dual combination target is higher because in this case, you're putting two drugs together, NBD1 needs to do more of the work in a two-drug combination requires more exposure than in the four-drug combination of the add-on. The key takeaway that you see from the PK slide here of 719 is that at every dose we tested with 719, it exceeded the add-on target of clinically meaningful benefit. And then every dose we tested at 40 mg or above, it exceeded the dual combination target. Now, if you look at the right-hand side, this is our CFHBE assay that measures chloride transport on the y-axis, and we've put this into a relative scale so you can see where the standard of care sits at the 1.0 point on the reference, which is Trikafta. That's the standard of care today. If you look at the teal hash line on the HBE curve, that teal line matches up with the lower teal line of an add-on. 719 is moving forward as an add-on to the standard of care. That teal line, that minimum clinical meaningful efficacy is defined by at least a 10 millimole sweat chloride improvement above the standard of care, which we also believe will translate into a three percentage point improvement in FEV1. So if you look at that minimum bar, it's about a 25% improvement over the standard of care When we map our PK for 719 added on top of Trikafta, you can see that maroon shaded area shows you what's possible as we add 719 on top. We believe we're confident we'll achieve that 10 millimoles of sweat chloride, and there's the potential we could deliver all the way up into wild-type levels of CFTR function. So very encouraging for us, which is why we're excited to see the results this summer on the precision CF study. A similar set of data for 451, which remember is the anchor to our dual combination strategy, you can see on the PK side, similar targets for an add-on and a dual combination. The key takeaway for 4.5.1 on the PK is that for every dose we tested at 75 milligrams or above, we exceeded the dual combination target, which is the path that 4.5.1 is taking. And then similarly, on the right-hand side, the CFHBE transport, chloride transport slide, you can see that when we translate the PK that we achieved with 4.5.1 into the CFHBE assay, that maroon shaded area tells us we're at a very good position in this two-drug combination potential where we're above the minimum bar of 10 millimoles of sweat chloride improvement and potentially all the way up into wild-type levels of CFTR function. So let's talk about the strategy, our clinical plan. I've alluded to this. We have two different approaches we're taking. We're leveraging 719 and 451 in two different ways to advance them in a way that best supports our clinical development strategy. 719 is the anchor to our add-on strategy up top that you see here. It's in the Precision CF study that is now fully enrolled. We expect to have data in the summer of 2026, and I'll talk about that design in a minute. And then we also have our dual combination strategy where 451 is the anchor in two different two-drug combinations, 451 plus 2222 and 451 plus 109. We expect to also have that data in the summer of 2026. We have two different strategic choices that we have to make as we gather this data in the summer of 2026. On the dual combination, the first strategic decision we have to make is which combination are we progressing into the next stage of development, which would be in CF patients. The goal of this healthy volunteer study is to help us make that determination of which combination moves forward based on two things, the safety and tolerability profile of each combination, and also the PK or exposure profile of these combinations. We are anchoring to the best benefit risk profile in these two combinations, looking to select the combination that gives us the highest potential for efficacy, but is also safe and well-tolerated at the doses we will move forward with. So again, that's the first decision we'll have to make with the data in the summer of 2026. The second decision we'll have to make is on the add-on. And this decision we will have to make when we see that data, if it is positive, we will decide whether we will continue to advance the add-on approach going forward into a phase 2b dose-ranging study. If the data is positive, we think that is an attractive option for patients. We've done the market research. It is commercially viable and attractive, but we want to see the data, ensure it's positive, and then we also want to ensure the capital is there to pursue both paths, both the add-on and the dual combination path. We've been encouraged by the investor feedback that we've received on the add-on, and if we hit that profile, that would be a meaningful option for patients. We've heard that from the community as well, but we want to ensure the capital is there to pursue both paths. So two different strategic choices for us going forward. Now let's just talk quickly about the design of the Precision CF study. This is a two-way crossover study that is powered to deliver at least a 10 millimole sweat chloride improvement, which will demonstrate improvement in CFTR function for people living with CF. It's an efficient, well-designed study that's going to create a really valuable amount of information for us. And at the end of the day, it's really three things that are important to us. As a two-way crossover, each patient becomes its own control, which gives us a lot of value. But as we look at what is the real outcome of this study going to do for Siona and for the community, the first is it's going to show the ability to drive sweat chloride lower by at least that 10 millimole sweat chloride, which will show us the improvement in CFTR function. And if we show that, we know that is clinically meaningful because of how the community has defined that meaningfulness in the past. 10 millimole sweat chloride improvement is meaningful because the expectation is we will also be able to deliver at least a 3 percentage point improvement in FEV1 in future studies. This has been consistently the feedback we've heard from the community that this would be an exciting profile if we can achieve that. It will also show that 719 as an NBD-1 stabilizer is mechanistically different from the components of Trikafta, the three-drug combination of Trikafta, that NBD-1 will be doing something different to improve the CFTR function so it's differentiated from but also synergistic with the components of Trikafta. And then the third piece that's very important is this is the first opportunity we will have to show the translation of our CF-HBE assay in CF patients. As I mentioned before, we have a high degree of confidence in our CF-HBE assay and its predictive power. This will be the first opportunity for us to show it. If we deliver that 10 millimole or more improvement, it will validate the HBE assay. And one last point of reference here. If you look at the Aleftrac, the most recent next-gen triple combination from Vertex, in their phase three study with homozygous patients, which is the same population we're studying in the precision CF study, Aleftrek delivered a three millimole sweat chloride improvement above Trikafta. We are targeting at 10. So just to keep that in mind, but we're very excited about the potential for this data in the summer of 2026 and what it means both from a strategic perspective for Siona, but also what it could mean for the community going forward. Let's talk about the commercial opportunity. I talked about unmet need. And this visual here is a post-marketing study done by the Cystic Fibrosis Foundation that is looking at sweat chloride. If you go all the way to the right, you can see Trikafta. The blue dots represent individual patients and their sweat chloride as measured on the y-axis. The blue dots represent prior to Trikafta. The black dots are patients after they've gone on Trikafta. Trikafta. And you can see the various sweat chloride improvement here. What is important to point out is if you look at that teal line at the bottom at the 30, that's where normal sweat chloride begins. Anything below 30 is normal sweat chloride. And here you can see only a third of patients on Trikafta achieve that normal sweat chloride bar that we've talked about in the past. So that leaves two-thirds still with room to improve their sweat chloride and their CFTR function. That's the ultimate goal for us, drive as many patients as we can into the normal CFTR function range by getting below the 30 millimoles of sweat chloride. This plot also informed our enrollment criteria as we thought about who to enroll in the precision CF study. We did not enroll anybody that was at normal CFTR function as defined by sweat chloride. There is a possibility we could drive even those patients to lower sweat chloride, but this precision CF study was not designed to do that. We selected patients whose sweat chloride was in the typical range, had a typical response to Trikafta to enroll in our study, and we're very pleased with the patients that have come in to the Precision CF study. And then I'll skip over this in the interest of time, but in the interest of commercialization, building on the unmet need, we do know that this is a large rare disease, right? This is a monopoly that exists today. Vertex is the only player in CF today. There's 100,000 patients, 90% of which have the F508 DEL mutation, which is the population we would be going after, just like Vertex. And what we hear from the community over and over again is the desire for more options. They want new and differentiated options that give them the ability to drive their sweat chloride lower, to improve their CFTR function in FED1. We think we have this opportunity with our NBD1 combination strategy to drive those two-thirds of patients to lower sweat chloride, improve their FAD1, and get more patients to normal CFTR function. If we can do that, again, in this market that's $12 to $13 billion today, growing to over $15 billion in the future, it's not only transformational for patients, but also significant commercial opportunity for Siona. So just to close out, we are in a very unique opportunity here to positively disrupt the CF market with a new opportunity driven by our our NBD-1 stabilizers in various combinations. We have our two-pronged approach, 719, as an add-on to the standard of care. The precision CF study, we're expecting data in summer of 2026. Everything's on track. The study is fully enrolled. We're excited for that data. And similarly, we have our parallel path of our dual combination strategy, where 451 is the anchor. We expect in the summer of 2026 to have that data as well that will enable us to make those two strategic decisions I mentioned before. Which of the dual combinations will we progress forward into a CF patient study and will we continue to develop the add-on approach going forward if the data is positive and the capital is there, that is our preference. So we are in a great position, the science is differentiated, and we have a great team, we're well capitalized, and we very much look forward to the summer exciting times ahead for Sionum. So I appreciate the time and we can now open it up for Q&A. Did we release the baselines of sweat chloride? improve their sweat chloride levels, even if they are below 30. But this is not the study to do that, right? We can do that. If you think about later stage studies, bigger studies, more patients, that's something we could test there. But for this precision CF study, nobody below 30 would be entered. And then if you look at the top end, you can see this distribution of dots that are, you know, a tail at the top end here. We don't know enough about those patients as to why they don't seem to be having the typical response to trikafta. So we're also excluding those higher higher values of sweat chloride from enrolling in the criteria here. Not because, again, we might be able to help those patients, and maybe NBD1 is a key to unlocking some additional sweat chloride improvements, but we just don't know enough about the biology of those patients to see if there's something different going on. So what we've enrolled in this first study, being a small, efficient study, is really right down the middle. Patients that have had a typical response to Trikafta, not at the normal levels, not still very high on their sweat chloride, but also enough dynamic range left in sweat chloride that we can drive them lower and achieve that minimum bar that we've set of at least a 10 millimole sweat chloride improvement. So that's the context that we've given. And again, as we think about later stage study, you can see about opening up that more to the sweat chloride enrollment. But for this one, you know, we feel very pleased about the profile of the patients that have enrolled in the study. So maybe we've hit an end. I appreciate again, everybody's time and attention. We're super excited about what's coming ahead for us the summer of 2026 a real opportunity to positively disrupt the CF market and do something transformational for people living with CF. Thank you again for your time. Jeffries, thank you for the invitation. Have a great day.