Good morning, and welcome to the Sionna Therapeutics conference call. At this time, all participants are in a listen-only mode. After today's presentation, there will be an opportunity to ask questions. You will need to press star one one on your telephone to queue. Please note that this event is being recorded. I will now turn the call over to Juliet Labadorf, Senior Director of Investor Relations. Juliet, you may now begin.
Thank you. Good morning, and welcome to today's conference call. Joining me are Mike Cloonan, 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 will 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.
Thanks, Juliet, 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 of SION-719 added to Trikafta, and our Phase 1 trial of SION-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 Sionna team for their incredible dedication, focus, and commitment. We are deeply disappointed to announce that 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 seven one nine as an add-on to standard of care.
The Phase 1 dual combination trial evaluating SION-451 in combination with SION-2222 and SION-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 SION-451 + SION-2222 dual combination. We will be data-driven and disciplined, including taking actions 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.
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 five, PreciSION CF Phase 2a proof-of-concept trial evaluated a 30 mg twice daily dose of SION-719 when added to Trikafta. This was a randomized, double-blind, placebo-controlled crossover trial in adults with CF who are homozygous for F508del on a stable dose of physician-prescribed Trikafta. After screening and a 14-day Trikafta run-in, participants received 14 days of SION-719 + Trikafta and 14 days of placebo+ 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 mmol/L , 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 F508del 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 to 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 SION-719 was added to background Trikafta, we observed a mean placebo-adjusted sweat chloride change of -1 mmol/L 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, SION-719 was generally well tolerated. SION-719 exposure was consistent with data from the Phase 1 trial of SION-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 SION-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, SION-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 SION-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 SION-719 as an add-on to standard of care. I will now turn to top-line results from the SION-451 Phase 1 healthy volunteers dual combination trial. On slide 10, we evaluated the safety, tolerability, and PK profiles of different dose combinations of SION-451 with the two complementary modulators, SION-2222 and SION-109. Dual combinations were studied in randomized, double-blind, placebo-controlled 14-day dosing cohorts with participants randomized three to one, 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 SION-451 + SION-2222 and SION-451 + SION-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, SION-451 + SION-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 SION-451 + SION-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 SION-2222.
The twice-a-day regimen had not been previously explored in clinical development. We identified SION-451 BID and SION-2222 QD as our preferred combination and regimen based on its favorable tolerability profile and exposure in this Phase 1 trial. All SION-451 cohorts with SION-2222 dosed 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 SION-2222 was dosed twice a day in combination with SION-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 infection. All events were transient and resolved without sequelae, and there were no additional liver-related findings, such as increases in bilirubin.
I will now hand things back to Mike for concluding remarks.
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 SION-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.
Thank you. If you have a question at this time, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Paul Matteis with Stifel. Your line is now open.
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? Were those decreases in Trikafta big enough to explain what happened here? Maybe just beyond that, what are the two to three working hypotheses that the Sionna team has right now, and when do you expect to have a conclusion and a conclusion around what the path forward is, if any, with NBD1? Thank you.
Thank you, Paul. This is Charlotte. I'll answer the first question and then I'll turn the second part over to Mike. As I mentioned and we announced, there was a noticeable and observable decrease in Trikafta levels when patients were dosed in 719 period compared to the placebo period. It is possible that it was of a magnitude that was large enough to have impacted the potential treatment effect. 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. There was some possible other more complex interaction, but it is real and observable and could potentially have impacted the outcome.
Paul, I'll take the second part. You asked the two to three things that, the hypothesis, and I think Charlotte mentioned one of them. We should just talk through that Trikafta exposure, we can't say yet what impact that has had. We're evaluating the patient-to-patient impact. With that, one of the things we're really trying to evaluate is there's something inherent in this study. In adding on top of Trikafta, did there derive differences that we didn't expect? 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. We had such a wide range of response here in terms of the sweat chloride outcomes, we really have to dig into exposure response, as Charlotte said.
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. There clearly was a difference in what we assumed coming out of our CF-HBE, and we built it around a 10 mmol sweat chloride improvement, and we obviously didn't deliver that. 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. That's probably the best hypothesis we have right now.
Thank you.
Thank you. Our next question comes from the line of Yatin Suneja with Guggenheim. Your line is now open.
Hey, guys. Thank you for taking my questions and research sentiment. Maybe just high-level question. How should we think about the assay that you have used? Any sort of thought on the assay and sort of the predictability of that? Does this data change your view? Maybe if you can compare and contrast the biology versus the assay. How should we think about the next step? What sort of decision you need to make before you decide the dual combo?
Yeah. Thanks, Yatin. It's Mike. I'll take that one, and obviously, Charlotte can chime in, too. As I was mentioning to Paul's question, that is absolutely, clearly something we have to look at is the translation here and what we can learn. As I said, 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 SION-719 PK and the exposures that we had set ahead of time in the study itself. Obviously, we didn't see that level of translation in the study itself. 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. That is absolutely critical, as I said, to help inform the decision that we have to make on SION-451 and SION-2222 and its path forward. With that dual combination, as Charlotte mentioned, the Phase 1 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 SION-451 + SION-2222 as the preferred combination. 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 our assay assumptions and what the path forward for the dual combination is.
And-
Go ahead, Charlotte.
Hi, Yatin, this is Charlotte. I would just add, really, 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 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 potential for NBD1 modulation. Really our question is a question about target engagement and exposure response and how we need to potentially modify that set of predictions.
Thank you. Our next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.
Good morning, guys. 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 into the increased variability there seen. 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 SION-451 data? 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 SION-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 SION-451 ? Thanks.
Yes, hi, Ritu. Your first question was about the sweat chloride variability. I just want to be maybe 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. 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 more noise to the system. It just makes it a little bit harder for us to tease through and identify clear patterns. That is still possible to do. Obviously for any potential trials in the future, we would take that into account.
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. I'll start with your 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 SION-451 /SION-2222 combination. It's really too early at this point to be hypothesizing about magnitudes or fold changes. We would be thinking about those things as we consider the next steps.
I'm sure people picked up on this, since we did announce today that the dose we did use in the 719 study was 30 milligrams. We had always referred to in the lower dose range. We disclosed that we used the 30 mg. Maybe just to build on Charlotte's point, in the Phase 1 healthy volunteer study of the duals, we used similar doses that we've used previously in the Phase 1's, right? You can see some relationship there that we have ability to have a higher dose clearly with SION-451 versus the 30. 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 SION-451 is competitive.
Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Good morning. Thanks for taking my question, 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, in the context of what you could learn. If there is the case here where the LCs truly are not translating, what that means for SION-451 , and just kind of the forward of this portfolio.
Hi, Salveen. I'll start that. This is Charlotte, I'll turn it over to Mike as well. 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, we're fortunate to have both placebo and active drug treatment periods for all of those 14 patients. It does allow us to try to, again, tease through potential exposure responses as well as confounding variables. As we've 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 really appears from the exposure and other data that there were some irregularities in the 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. As you might expect, there are both some statistical tools and some post hoc and ad hoc ways of looking at the data. Looking with or without outliers, for example, in ways that are both rigorous clinically and statistically that we'll be deeply investigating.
Yeah. Maybe something just to add to what Charlotte said. As I said before, part of this analysis is also trying to figure out what is an outcome of this specific study, adding on top of Trikafta 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 + SION-719 versus Trikafta and placebo? We really need to tease that relationship out to understand if there's something inherent in this study when you put these four drugs together. That could have impacted the sweat chloride response. That we can understand, was this true translation or was it something to do with the four-drug combination? The other part is we do have, as I mentioned, wide distribution of sweat chloride outcomes.
In some patients, their exposure matches. 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.
Thank you. Our next question comes from the line of Chris Raymond with Raymond James. Your line is now open.
Thanks. Really sorry also to see this data. Just a couple of questions, I guess. Have you seen any individual responses to the add-on therapy that met that 10 mmol/L 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. 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 SION-719? Thanks.
Thank you, Chris. It's Mike. On your first question, I'll let Charlotte talk about the time on Trikafta. At this point, we see is a wide distribution. Our mean was that minus one, but there is a wide variation. We had patients responding, we had patients with some placebo effect, we are really trying to understand that dynamic. Again, some of the things Charlotte's referencing, each individual patient almost has its own story. We got the data so recently, we haven't been able to tease out each individual data set of that patient to really understand what are their confounders. Does that have an impact, or does it not have an impact on sweat chloride? That is the work ahead of us.
We have a total sense of urgency here to get this down pat because we have some decisions to make, and it's important. We really entertain this study because we believe in the outcome, and we're disappointed in the way this played out. 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 time on Trikafta?
Yes. Hi, Chris. Charlotte. All of the participants had to have been on a stable standard label dose of Trikafta for at least three months before screening and then had another weeks of the run-in on Trikafta. We don't capture in our database, we didn't capture how long they had been on Trikafta before the screening period, but they're all on Trikafta for at least four months. 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 looked like sweat chloride changes.
Okay. Thank you.
Thank you. Our next question comes from the line of Jon Wolleben with Citizens JMP. Your line is now open.
Hey, guys. Thanks for taking the questions. I'm wondering if you'd talk more about the target exposures you did see with SION-451 and how they relate to what you saw with SION-719. Then also any best estimates for when we could get an update on next steps. Thanks.
Hi, this is Charlotte. I'll speak first to the target exposures. It's early days as we tease through, again, what Mike describes as our translational framework. As we've said, for the SION-451 exposure, 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 SION-451 exposures.
Yeah. Next steps. Again, for us, it is 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 have talked about. The variability, the confounding factors, the translational model here, coming back with our decision on the path forward for SION-451 and SION-2222. I did want to come back, Chris, I do not know if maybe my answer to your question on that when I said wide distribution, we did have patients above 10. Just to be clear, I was just trying to say that distribution is wide from the responders and non-responders, which we have got to dig into, but I did not want to leave you hanging on that part of the question.
Thank you. Our next question comes from the line of Gaurav Maini with LifeSci Capital. Your line is now open.
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 SION-451, any color we could get on just how you are thinking about dose strategy moving forward? Given the safety with the SION-719 add-on was noted to be okay, would there be consideration for maybe using a sort of mid to high dose range as we think about SION-451 combos? Thank you.
Gaurav, I will start. I would 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 SION-451 and SION-2222. I think what we did learn from the study is that the SION-451 BID plus the SION-2222 QD was well-tolerated and it exceeded our PK targets that we had set prior to the PreciSION CF data. That was positive. We are pleased with the well-tolerated doses that we did test there. We will come back. We will talk about the ranges when we have a better plan forward, right? What we are going to do with SION-451 and SION-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 SION-451 and SION-2222.
Thank you.
Thank you. Our next question comes from the line of Kambiz Yazdi with BTIG. Your line is now open.
Hi, team. Thank you so much for the questions and echoing my colleagues' sentiments. Two questions for me. On PreciSION CF, for the safety sequence two patients showed a little bit higher TEAE rates compared to sequence one. Do you have any interpretation at this point for the asymmetry across the crossover sequences? Then maybe just more broadly, can you walk us through what molecularly distinguishes SION-719 and SION-451 ? If you believe those molecular differences could provide a meaningful difference in clinical outcome as you may move SION-451 forward. Thank you so much.
Hi, this is Charlotte. I'll start with both of these and then turn it over to Mike. 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. There are going to be numerical differences in percentages of outcomes every time you take two slices of data or replicate experiments. We don't see this as meaningful. We really see the safety and tolerability profile as across the study as looking like as we could have hoped and expected. The other question is about SION-719 versus SION-451. Maybe I'll step back because, maybe just to level set, we are probing the SION-719 PreciSION CF data deeply to determine what the potential impact is on our translational framework.
At this point, we really would not say that there was something about SION-719 specifically that led to a negative outcome. I'll just reiterate, we believe that this is related to target engagement and exposure response. We don't view the potential if we think about SION-451 and SION-2222, we think about that as a very different context to address NBD1 modulation and biology, not that we might need a different molecule to do that.
Okay.
Thank you. Our next question comes from the line of Debanjana Chatterjee with Jones Trading. Your line is now open.
Hello, good morning. This is Avni on for Debanjana . Again, reiterating everyone's sentiments, really sorry to hear about the data. I just wanted to ask, in terms of the financing strategy and timeline for a potential Phase II trial, what are we thinking with the chosen SION-451 / SION-2222 combo?
Financing strategy and cash runway?
Yeah. As Mike mentioned earlier, we ended Q2 with approximately $268 million in cash. We did announce this morning that we will be taking actions to preserve capital and extend that runway, and we would anticipate providing an update on that cash runway once we finalize more of the details around the SION-451 , SION-2222 next steps.
Thank you.
Thank you. That is 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.