Capital Markets Day Transcript - SION 2026-08-10

Operator

Good morning, and welcome to the Siona Therapeutics conference call. At this time, all participants are in a listening mode. After today's presentation, there will be an opportunity to ask questions. You will need to press star 11 on your telephone to queue. Please note that this event is being recorded. I will now turn the call over to Juliette Labrador, Senior Director of Investor Relations. Juliette, you may now begin.

Yatin Suneha, Analyst — Guggenheim

Thank you. Good morning, and welcome to today's conference call. Joining me are Mike Clunan, our President and Chief Executive Officer, and Charlotte McKee, our Chief Medical Officer. Also joining us for the Q&A session is Elena Ridloff, our Chief Financial Officer. Following our prepared remarks, we'll open the call to questions. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC, as well as any subsequent SEC filings. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I will turn the call over to Mike Cloonan, our CEO.

Mike Cloonan, CEO

Thanks, Juliette. And good morning, everyone. Thank you for joining us. Today, we are announcing top-line data from two clinical programs, our Precision CF Phase 2A proof-of-concept trial SCION 719 added to Trikafta and our phase 1 trial of SCION 451-based proprietary dual combinations. Before we discuss the results, I would like to thank the people who participated in these studies, their families, and all those involved in executing the trial. I also want to recognize the Siona team for their incredible dedication, focus, and commitment. We are deeply disappointed to announce that the Precision CF phase 2A trial did not meet its key activity endpoint as measured by change in sweat chloride. Given these data, we are not continuing development of 719 as an add-on to standard of care. The phase one dual combination trial evaluating 451 in combination with 2222 and 109 achieved its safety, tolerability, and PK objectives, including exceeding target exposure that we had determined prior to the precision CF outcome. We are actively analyzing the Phase 2A data and our translational framework to help assess the potential profile and next steps for 451 plus 2222 dual combination. We will be data-driven and disciplined, including taking action to preserve capital. Charlotte will now walk us through the results, and I will return to discuss our next steps. After that, we will open the call for Q&A.

Charlotte McKee, Board Member

Thank you, Mike. I have spent many years committed to developing medicines to help improve the lives of people with CF, and I am deeply and personally disappointed in today's announcement. Now, we'll look at the data. Turning to slide 5, the Precision CF Phase 2A proof-of-concept trial evaluated a 30 mg twice-daily dose of 719 when added to Trikafta. This was a randomized, double-blind, placebo-controlled crossover trial in adults with CF who are homozygous for F508-DEL on a stable dose of physician-prescribed Trikafta. After screening and a 14-day Trikafta run-in, participants received 14 days of 719 plus Trikafta and 14 days of placebo plus Trikafta in random order, with a 28-day washout between treatment periods. The crossover design enabled us to compare changes from baseline during the active and placebo periods in the same participants. The primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetics and change in sweat chloride, which is an important biomarker of CFTR function. We powered the trial for a sweat chloride improvement of at least 10 millimole per liter, a threshold we believe represents clinically meaningful benefit based on an in-depth analysis of the literature and thought leader and community feedback. On slide six, we summarize baseline and demographic characteristics. The trial enrolled 15 participants, all homozygous for the F5OE-DL mutation, and stable on Trikafta for at least three months before screening. Baseline sweat chloride and other demographic characteristics were consistent with the population we intended of the study. Adults with CF who had a typical response to standard of care but still had room for improvement in CFTR function. Turning to slide seven, I'll start with the top line results. When 719 was added to background Trikafta, we observed a mean placebo-adjusted sweat chloride change of minus one millimole per liter with a p-value of 0.7. This was below the threshold we had defined as clinically meaningful, it was not statistically significant, and it did not demonstrate the level of additional CFTR functional improvement we expected. When added to Trikafta for 14 days, 719 was generally well tolerated. 719 exposure was consistent with data from the Phase I trial of 719 alone in Healthy Volunteers, and mean Trikafta exposures were consistent with published data. We observed potential trial confounders, including higher than expected variability in individual sweat chloride levels and differences in Trikafta exposure levels between the 719 and placebo periods at the individual participant level. We are actively assessing these variables. We do not believe our findings will change the outcome of the Precision CF study, but we believe it's important to understand them fully to inform our translational framework and potential next steps for the 451 dual combination. Turning to safety on slide 8, 719 was generally well tolerated when added to Trikafta. Most treatment emergent adverse events were mild to moderate. There were no serious adverse events and no clinically meaningful trends in adverse events overall, including no trends in liver function events. We observed one grade 3 liver function test increase at the start of the 719 treatment period before dosing, which resolved before the end of treatment. One patient discontinued treatment unrelated to an adverse event. We continue to analyze the precision CF data, including potential trends and correlations, to better understand what contributed to the outcome. Taken together, however, the results do not support advancing 719 as an add-on to standard of care. I will now turn to top-line results from the 451 Phase I Healthy Volunteers Dual Combination Trial. On slide 10, we evaluated the safety, tolerability, and PK profiles of different dose combinations of 451 with the two complementary modulators, 2-2-2-2 and 1-0-9. Dual combinations were studied in randomized, double-blind, placebo-controlled 14-day dosing cohorts with participants randomized 3-to-1 active versus placebo. Most cohorts were dosed in the fasted state with one fed cohort dosed in each dual combination arm. 120 total participants were dosed across 10 dual combination cohorts, with 60 participants in five cohorts in each combination arm. We identified combinations of both 451 plus 2222 and 451 plus 109 that were generally well tolerated and achieved the targeted PK exposures set before the precision CF data readout, So the study met its safety, tolerability, and PK goals. Based on the totality of the data and target coverage observed, 451 plus 2222 was identified as the preferred dual combination. Exposures of both drugs in the combination were similar to what was observed in trials of each drug studied alone. On slide 11 are further details of the safety and tolerability profile of 451 plus 2222. One of our goals in this trial was to explore dose ranges to probe the safety and tolerability and potential efficacy of our dual combinations and to optimize exposure at well-tolerated doses. In our dose exploration, we evaluated both once-daily and twice-daily doses of 2-2-2-2. The twice-a-day regimen had not been previously explored in clinical development. We identified 451-BID and 2222-QD as our preferred combination and regimen based on its favorable tolerability profile and exposure in this Phase I trial. All 451 cohorts with 2222 dose once a day were generally well tolerated, with all treatment emergent adverse events mild to moderate in severity. There were no serious adverse events and no treatment emergent events related to elevated liver function tests. One participant discontinued dosing due to a moderate rash. When 2222 was dosed twice a day in combination with 451, two participants discontinued dosing due to dose-limiting events of increases in liver function tests and flu-like symptoms. Both cases were confounded by other factors, including potential infections. All events were transient and resolved without sequelae, and there were no additional liberal-related findings, such as increases in billy risen. I will now hand things back to Mike for concluding remarks.

Mike Cloonan, CEO

Thanks, Charlotte. As a reminder, at the end of the second quarter, we had approximately $268 million in cash. We are currently undertaking actions to preserve capital. I want to close by acknowledging that this is not the outcome that the CF community, our investigators, our shareholders, or our team wanted to see. We built these programs around a compelling scientific hypothesis and a meaningful goal to improve CFTR function for people living with CF who still need better options. That is what makes the results of the precision CF study so difficult. We are interrogating the results of precision CF to assess the potential profile and next steps for the 451 and 2222 dual combination. We will be disciplined and data-driven as we make decisions on the best path forward, and we anticipate providing further insight in the near term. Clinical research only happens because people are willing to participate, partner, and believe in the possibility of progress. We are incredibly grateful for that trust. Thank you all for joining us today. I will now ask the operator to open the call for questions.

Operator

Thank you. If you have a question at this time, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Our first question comes from the line of Paul Matias with Stiefel. Your line is now open.

Paul Matias, Analyst — Stifel

Hey, thanks for taking my questions, and sorry to see the results. Can you maybe quantify a little bit more the changes in Trikafta that you saw? Like, is that, were those down, I guess, decreases in TROCAPs are big enough to explain what happened here? And then maybe just beyond that, like, what are the two to three working hypotheses that the Siena team has right now? And when do you expect to sort of, I guess, have a conclusion and a conclusion around what the path forward is, if any, with NBD1?

Charlotte McKee, Board Member

Thank you, Paul. This is Charlotte. I'll answer the first question, and then I'll turn it over, turn the second part over to Mike. So, as I mentioned and we announced, there was a noticeable and observable decrease in Trikafta levels when patients were dosed in the 719 period compared to the placebo period. And it is possible that it was of a magnitude that was large enough to have impacted the potential treatment effects. We're still doing a lot of exposure response work, and we'll be diving into that much more deeply. I will just say, based on the patterns and the individual profiles, that impact does not appear to be driven primarily or all by CYP3A4 induction. So there was some possible other more complex interaction, but it is real and observable and could potentially have impacted the outcome.

Mike Cloonan, CEO

Yeah, Paul, I'll take the second part. So you asked the two to three things that, you know, the hypothesis, and I think Charlotte mentioned one of them, right? We should just talk through so that tricap exposure, we can't say yet, right, what impact that has had. We're valuing the patient-to-patient impact. But with that, one of the things we're really trying to evaluate is there's something inherent in this study, right, and adding on top of Trikafta, did there drive differences that we didn't expect? And that response is one of them. There were also sweat chloride variations that Charlotte talked about prior, and we're looking at that as well. And we had such a wide range of response here in terms of the sweat chloride outcomes, and so we really have to dig into exposure response, as Charlotte said. So we have to do a deep, deep interrogation of this, because one of the things we also want to make sure we can do is learn from the data that we do have how the translational model should be adjusted to help us be more precise, right? Because there clearly was a difference in what we assumed coming out of our ICA-HBE, and we built it around a 10-millimole sweat chloride improvement, and we obviously didn't deliver that. So we need to do all of this work to really help assess what the path and the potential is for the dual combination moving forward. So that's probably the hypothesis we have right now.

Paul Matias, Analyst — Stifel

Thank you.

Operator

Thank you. Our next question comes from the line of Yatin Suneha with Guggenheim. Your line is now open.

Mike Cloonan, CEO

Hey, guys. Thank you for taking my questions. And we should have some good sentiment. Maybe just I have a question. I mean, how should we think about the essay that you have used, any sort of thought on the assay and sort of the predictability of that? Does these data change your view? Maybe if you can, you know, compare and contrast the biology versus the assay, and how should we think about sort of the next step? Like, what sort of decision you need to make before you sort of decide the dual combo? Yeah, thanks, John. That's Mike. I'll take that one and obviously I can chime in too but so as I was mentioning to Paul's question that is absolutely clearly something we have to look at the translation here what we can learn as I said we we had a degree of confidence that we were going to achieve at least that 10 millimoles based on our assay predictions we achieved the 719 pk and the exposures that we had said ahead of time in the study itself and obviously we didn't see that that level of translation in the study itself so we need to go deep into the data now we've got 14 patients that we can evaluate that completed the study. We have to look deeply at each patient's response, what exposure they achieved, and really try to map back to the assay around what tweaks we can make or learnings we can have to improve that prediction. And that is absolutely critical, as I said, to help inform the decision that we have to make on 451 and 2222, and its path forward. You know, with that dual combination, as Charlotte mentioned, the phase one study achieved the safety, tolerability, and PK profile that we had set out ahead of the precision CF study, and it enabled us to select 451 plus 2222 as the preferred combination. But we really want to take the time and pause now with this data in hand to really make sure we deeply interrogate it to help inform, you know, our assay assumptions and what the path forward for the dual combination is.

Charlotte McKee, Board Member

And maybe I would – hi, yes, and this is Charlotte – I would just add, really, I would just double-click on this exposure response and target engagement question. It's really what we're probing very, very deeply in these data because, as you know, and, you know, we've all discussed, there's a wealth of literature, scientific literature, biology from multiple labs around the world, and including our data, demonstrating the biology and, you know, potential for NBD1 modulation. And so really our question is a question about target engagement and exposure response and how we need to potentially modify that set of predictions.

Operator

Thank you. Our next question comes from the line of Ritu Baral with T.D. Cowan. Your line is now open.

Avni, Analyst — Jones Trading

Good morning, guys, and thanks for the clarity and insight here this morning. A couple questions. One is basically Paul's question, but applied to the sweat chloride. and basically any insight on into the increased variability they're seeing. Obviously, it's a notoriously variable measure in individual patients per the KOLs. And is there any insight in how to control that potentially for the 451 data? And if I could sneak a second one in here. Given, Charlotte, your discussion of exposure response, right, as you are thinking of the doses of 719 used, the potency and the exposure limitations, the admin limitations of that drug, and what you intend to use for 451 going forward, is there a multiple, pharmacokinetically, a multiple of activity that you guys have estimated for what could be the increased activity at NBD1 in the trials going forward with 451? Thanks.

Charlotte McKee, Board Member

Yes, Tyra too. So your first question was about the sweat chloride variability. So I just want to be, you know, may be clear that definitely was something we observed was more variability. That variability alone in the sweat chloride, we do not believe drove the outcome or the results from the study. It does make it more difficult with this variability to tease through the underlying exposure response and identify what might be a lower than predicted treatment effect and so that is where fortunately there are some statistical tools we can use and we have been bringing those to bear the variability is just it adds some it adds more noise to the system so it just makes it harder a little bit harder for us to tease through and identify clear patterns, but that is still possible to do. And, obviously, as we, you know, if there are any, for any potential trials in the future, we would take that into account, but that was not, that doesn't change the outcome of the study, and that was not the critical factor. We do believe it was the magnitude of treatment effect and really the exposure response that was the critical factor here. And I'll just, I'll start with the second question. Again, we're continuing to evaluate the translational framework and determine what the impact and potential next steps would be, as we said, for the 4-5-1-2-2-2-2 combination. It's really too early at this point to be hypothesizing about magnitudes or fold changes. We would, you know, be thinking about those things as we consider the next step.

Mike Cloonan, CEO

Yeah, maybe just to, you know, I'm sure people picked up on this. We did announce today that the dose we did use in the 719 study was 30 milligrams. We had always referred to it in the lower dose range. We disclosed that we used the 30 milligrams. and maybe just to build on Charlotte's point, in the phase one healthy volunteer study of the duals, we used similar doses that we had used previously in the phase ones, right? So you can see some relationship there that, you know, we have ability to have a higher dose, clearly, with 451 versus the 30. But as Charlotte said, we need to do more work, right, to confirm some of the assumptions that we have on the dual and ensure that the profile is competitive.

Operator

Thank you. Our next question comes from the line of Salveen Richter, with Goldman Sachs. Your line is now open.

Charlotte McKee, Board Member

Good morning. Thanks for taking my question, and I'm sorry to see the data as well. Perhaps just in the context of the confounding factors here, the translational aspect, the PK exposure, the DDIs, walk us through the scenarios for the forward here, like what you're, you know, in the context of, you know, what you could learn. And, you know, if there is the case here where the essays truly are not translating, what that means for 451 and just kind of the forward of this portfolio. Hi, Selvina. I'll start that. This is Charlotte and an alternative to Mike as well. Maybe just you asked about what we might learn that might inform what we might do in the future. Just as an example, as Mike said, we have these 14 participants, and we are fortunate to have both placebo and active drug treatment periods for all of those 14 patients. So it does allow us to try to, again, teased through potential exposure responses as well as confounding variables. As we mentioned, the differential exposures of trikafta in the treatment periods is something we're paying a lot of attention to. There also were individual instances, isolated instances, where it has, it really appears from the exposure and other data that there wasn't, there were some irregularities in background standard of care compliance. Again, these appear to be isolated instances, but those in a study where there are 14 individuals, those can be informative. And so, as you might expect, there are both some statistical tools and some post-talk and ad hoc ways of looking at the data, you know, looking with or without outliers, for example, in ways that are both rigorous clinically and statistically that we'll be deeply investigating.

Mike Cloonan, CEO

Yeah, maybe something just to add to what Charlotte said. Again, as I said before, part of this analysis is also trying to figure out what is an outcome of this specific study, right? Adding on top of TriKalp and what Charlotte mentioned around the exposures, is there a difference in what we see in the sweat chloride results if there were differences at the individual level when they were on Trikafta plus 719 versus Trikafta and placebo. We really need to tease that relationship out to understand is there something inherent in this study when you put these four drugs together, right, that could have impacted the sweat chloride response. And so that we can understand was this true translation or was it something to do with the four-drug combination? And then the other part is we do have a dimension-wide distribution of sweat chloride outcomes. And some patients, their exposure matches, right? And so there is this variation that we've got to understand why is there this distribution that's very different on a mean basis. We have to get into the individual level to really tease out and what we can learn to get this right for the next time. Thank you.

Operator

Thank you. Our next question comes from the line of Chris Raymond with Raymond James. line is now open.

Chris Raymond, Analyst — Raymond James

Hey, thanks. And I'm really sorry also to see this data. Just a couple questions, I guess. Have you seen any individual responses to the add-on therapy that met that 10 millimole per liter bar for success? Did anyone in the placebo group, I guess, hit that bar as well? I'm just kind of curious if there's anything you could tell us about the shared baseline characteristics of patients that did or didn't have a response. And maybe also a second question, can you comment if there's any correlation between the amount of time a patient was on Trikafta and the benefit or lack of benefit of 719? Thanks. Yeah, thank you, Chris. It's Mike.

Mike Cloonan, CEO

So on your first question, I'll let Charlton talk about the time on Trikafta. So, you know, at this point, what we're talking, we see is a wide distribution, right? Our mean was that minus one, but there is a wide variation, right? We had patients responding, we had patients with some placebo effect, and so we are really trying to understand that dynamic. And again, some of the things Charlotte's referencing, each individual patient almost has its own story. And we just haven't been able to, we got the data so recently, we haven't able to tease out each individual data set of that patient to really understand what are their confounders, right? And does that have an impact or does it not have an impact on the sweatboard? And that is the work ahead of us, We're going to be – we have a total sense of urgency here to get this down fact because we have some decisions to make, and it's important, right? We really entertain this study because we believe in the outcome, and we're disappointed in the way this played out. But there is a lot of data that we can dive into here that we may get some key learnings, and that will help us assess that distribution curve. Do you want to talk about the TriKepta – time on TriKepta?

Charlotte McKee, Board Member

Yes. Hi, Chris, Charlotte. But we – all of the participants were – had to have been stable on their – on a stable standard labeled dose of Trikafta for at least three months before screening and then had another four months or another four weeks of the run-in on Trikafta. We don't capture in our database, we didn't capture how long they had been on TriCAPTA before the screening period, but they're all on TriCAPTA for at least four months. And at least at this stage, as we're diving into the data, we don't see any obvious baseline characteristics, et cetera, that would account for what Mike described as definitely a spectrum of what looks like sweat chloride changes.

Chris Raymond, Analyst — Raymond James

Thank you.

Operator

Thank you. Our next question comes from the line of John Willobin with Citizens GMP. Your line is now open.

Yatin Suneha, Analyst — Guggenheim

Hey, guys. Thanks for taking the questions. Wondering if you could talk more about the target exposures you did see with 451 and how they relate to what you saw with 719, and then also any best estimates for when we could get an update on next steps.

Charlotte McKee, Board Member

Hi, this is Charlotte. I'll speak first to the target exposures. So, it's early days as we tease through, again, what Mike described as our translational framework. So, what we can, you know, what, as we've said, for the 451 exposures, we were well into the predicted range of target exposures based on the pre-precision CF data targets. As we work through this framework, we'll be assessing how that translates back and how that impacts how we view the 451 exposures.

Mike Cloonan, CEO

And then next steps. So, again, for us, it's deep dives on this data. We have an opportunity to pause and really go deep on this data and to assess all the things we've talked about. The variability, the confounding factors, the translational model here. and then coming back with our decision on the path forward for 451 and 2222. I did want to come back first. I don't know if I – maybe my question to you or my answer to your question on that when I said wide distribution, we did have patients above 10, right, just to be clear. I was just trying to say that distribution is wide from the responders and non-responders, which we've got to dig into, but I didn't want to leave you hanging on that part of the question.

Operator

Thank you. Our next question comes from the line of Gaurav Manai with LifeSci Capital. Your line is now open.

Mike Cloonan, CEO

Hey, good morning. Really sorry to hear about the outcomes here on Precision. Maybe just a quick one from me. As the team thinks about the path forward for 4.5.1, any color we could get on just how you're thinking about dose strategy moving forward? You know, given the safety with the 7.1.9 add-on was noted to be okay, kind of would there be consideration for maybe using a sort of mid to high dose range as we think about 4.5.1 combos? Thank you. Yeah, Gaurav, I'll start. I'd say it is early days, right? We want to do this analysis first, right, before we really start to lock in what that next steps are for 451 and 2222. I think what we did learn from the study is that the 451 BID plus the 2222 QD was well-tolerated, and it exceeded our PK targets that we had set prior to the precision CF data, and so that was positive. We're pleased with the well-tolerated doses that we did test there. So we will come back, you know, we will talk about the ranges when we have a better plan forward, right, what we're going to do with 451 and 2222. We really do need to do this work first, take the time now, pause. We have this opportunity to really evaluate what happened in Precision CF to best inform what comes next for 451 and 2222.

Chris Raymond, Analyst — Raymond James

Thank you.

Operator

Thank you. Our next question comes from the line of Kambiz Yazdi with U.S. Bancorp BTIG. Your line is now open.

Mike Cloonan, CEO

Hi, team. Thank you so much for the questions and echoing my colleague's sentiment. Two questions for me on precision CF. For the safety, sequence 2 patients showed a little bit higher TEAE rate compared to sequence 1. Do you have any interpretation at this point for the asymmetry across other sequences? And then maybe just more broadly, can you walk us through what molecularly distinguishes 7-1-1, 1-9, and 4-5-1, if you believe those molecular differences could provide a meaningful difference in clinical outcome as you may move 4-5-1 forward? Thank you so much.

Charlotte McKee, Board Member

So, hi, this is Charlotte. I'll start with both of these and then turn it over to Mike. So, your question, your first question is about the rate of TEAEs in sequence one versus sequence two. From our perspective, we don't see those TEAE percentages or incidences as meaningfully different. That is just, you know, there are going to be numerical differences in percentages of outcomes every time you take two slices of data or replicate experiments. So, we don't see those as meaningful. We really see the safety and tolerability profile as, you know, across the study as looking, like, as we could have hoped and expected. The other question is about 719 versus 451. Maybe I'll – we'll step back because maybe just to level set, we are probing the 719 precision CF data deeply to determine what we would – you know, what the potential impact is on our translational framework. We, at this point, we really do not, would not say that there was something about 719 specifically that led to a negative outcome. We, I'll just reiterate, I really believe, we believe that this is related to target engagement and exposure response. months, so we're not, we don't view the potential if we were, if we think about 451 and 2222, we think about that as a very different context to address NBD1 modulation in biology, not a different, not that we might need a different molecule to do that.

Operator

Thank you. Our next question comes from the line of Devanjana Chatterjee with Jones Trading. Your line is now open.

Avni, Analyst — Jones Trading

Hello. This is Avni on for Devanjana.

Yatin Suneha, Analyst — Guggenheim

Again, reiterating everyone's sentiments. Really sorry to hear about the data.

Avni, Analyst — Jones Trading

I just wanted to ask, in terms of the financing strategy and timeline for a potential phase two trial, what are we thinking with the chosen 451-222 combo?

Mike Cloonan, CEO

I think strategy and cash runaway.

Charlotte McKee, Board Member

Yeah, so as Mike mentioned earlier, we ended Q2 with approximately $268 million in cash.

Avni, Analyst — Jones Trading

We did announce this morning that we'll be taking actions to preserve capital and extend that runway.

Charlotte McKee, Board Member

And we would anticipate providing an update on that cash runway once we finalize more of the details around the 451-222 next steps.

Avni, Analyst — Jones Trading

Thank you.

Operator

Thank you. That's all the time we have for today. Thank you for participating in today's conference call. This concludes today's program. You may all disconnect, and have a good day.