Sionna Therapeutics, Inc. Common Stock Study result

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 IIa proof-of-concept trial of SION-719 added to Trikafta, and our phase I 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 the PreciSION CF phase IIa 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 I 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 IIa data and our translational framework to help assess the potential profile and next steps for SION-451 plus 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, the PreciSION CF phase IIa 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 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 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 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, SION-719 was generally well tolerated. SION-719 exposure was consistent with data from the phase I 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 I 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 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 5 cohorts in each combination arm.

We identified combinations of both SION-451 plus SION-2222 and SION-451 plus 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 plus 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 plus 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 I 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.