Sionna Therapeutics, Inc. Common Stock Status update

Good afternoon, 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. Elena Ridloff, our Chief Financial Officer, will also join us for the Q&A session. Following our prepared remarks, we will open the call for 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 and 8-K 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.

Thanks, Julia, and good afternoon, everyone. Thank you for joining us. Today, we are discussing two important updates, the findings from our comprehensive post hoc analysis of the PreciSION CF Phase IIa trial following top-line results announced in August, and how these findings informed our decision to advance SION-451 plus SION-2222 into the next stage of development. Our conviction in NBD1 stabilization remains strong. The post hoc analysis deepens our understanding of the NBD1 biology and target engagement and identified important trial learnings, giving us a clear and disciplined path forward. Several findings were particularly important. First, we identified three participants with PK patterns consistent with dosing non-adherence that disproportionately affected the original result. Excluding those participants, the mean placebo-adjusted reduction in sweat chloride was up to 8.6 millimoles per liter, which we believe is consistent with NBD1 biological activity and target engagement.

Second, even after adjusting for those participants, we identified two factors specific to the four-drug combination of SION-719 plus Trikafta that may have blunted the observed effect. Lower exposures of the Trikafta components during the SION-719 treatment period and a possible biological interaction with the potentiator Trikafta, ivacaftor. Together, these findings may help explain why SION-719 did not demonstrate its potential when added to Trikafta, and why we believe our NBD1-anchored dual combination without Trikafta or a potentiator could behave differently. Combined with the favorable phase I safety, tolerability, and PK results for SION-451 + SION-2222, we believe the post hoc analysis supports advancing the dual combination into AscenSION CF, an open-label phase IIa proof-of-concept trial expected to initiate in the first quarter of 2027. We are focusing our organization and capital on that dual combination program.

This includes the difficult decision to reduce our workforce by 46% and other cost-saving actions, which are expected to extend our cash runway into the second half of 2029 and to support execution of the dual combination strategy. Before moving forward, I want to recognize the Sionna colleagues who will be leaving the company as part of this restructuring. We are deeply grateful for your dedication, resilience, and contributions to our mission. I also would like to thank the CF community for the outreach over the last several weeks that has provided inspiration to our team and a strong reminder of the unmet need that remains for people living with CF. With that, I will turn the call over to Charlotte to walk through the analysis supporting our decision and our go-forward plan.

Thank you, Mike. As a reminder, PreciSION CF was a randomized, double-blind, placebo-controlled, two-way crossover trial evaluating 30 milligrams of SION-719 twice daily when added to physician-prescribed Trikafta in adults with CF homozygous for F508del. 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 a randomized order with a 28-day SION-719 washout between treatment periods. 14 participants completed both periods. The primary endpoint was safety and tolerability, which we described when we announced the top-line data. Secondary endpoints included pharmacokinetics and change in sweat chloride, an important biomarker of CFTR function. Two sweat chloride analyses were pre-specified in our protocol. The primary analysis was change in sweat chloride from study day one, and the secondary analysis was change in sweat chloride from the baseline of each treatment period.

We believe the secondary analysis using the baseline of each treatment period is most appropriate for this data set, given the PK and sweat chloride variability we observed. Turning to slide 6, following announcement of the top-line data in August, we conducted a thorough, disciplined post hoc review of the trial, as Mike mentioned. We evaluated multiple dimensions of the data, including PK and sweat chloride patterns in individual participants and in subsets. The potential impact of baseline and other characteristics and exposure response analyses. There are three factors we believe provide a reasonable and consistent interpretation of the data and potential confounders that may have impacted the results. Three participants had patterns of drug levels and sweat chloride values at key study time points that were consistent with dosing non-adherence, and we believe confounded the trial outcome.

When we adjust for those participants, we see what we believe is evidence of target engagement and NBD1 activity, albeit still at a lower level than what we predicted. Second, we saw consistently lower levels of all three components of Trikafta at the end of 719 treatment periods. The goal of this trial was to evaluate 719 on top of stable Trikafta levels, and this is not what consistently happened. While the implications are not completely clear, this finding suggests that lower Trikafta exposures may have reduced the impact of NBD1 stabilization. Finally, we have reviewed the non-clinical data in light of the trial outcome, which led us to an emerging hypothesis that combining 719 with Trikafta, and specifically with a potentiator, may have unexpectedly blunted the ability to improve CFTR function further with an NBD1 stabilizer.

Slide seven shows waterfall plots of individual participant-level sweat chloride changes for all 14 participants, calculated from each treatment period baseline. On the left is the 719 period, the placebo period is in the middle, and placebo-adjusted changes are shown on the right. The three outlier participant sweat chloride changes are shown here in the gray bars. On slide eight are more details about these three participants. Two had unmeasurable or unusually low levels of the components of Trikafta at the start of the placebo period after the 719 washout, and expected levels of Trikafta at the end of the placebo period, with very large improvements in sweat chloride over this period. We believe these participants' placebo effects were consistent with non-adherence with dosing at the beginning and confounded the trial results.

A third participant had unmeasurable 719 levels at the end of the 719 period, which was inconsistent with levels from the other participants and from healthy subjects given the same range of doses, and we believe this participant's data further confounded the trial outcome. Importantly, we did not identify similar confounding patterns in any other participants. When we removed these three PK outlier participants in a post hoc analysis, shown here on slide nine, we saw what we believe are consistent patterns in the data that indicate target engagement and NBD1 stabilization. During the 719 period here on the left, most participants had a numerical reduction in sweat chloride, while during the placebo period in the middle, sweat chloride changes appear very balanced, as you would expect. In this post hoc analysis, the placebo-adjusted changes also trend towards an improvement in sweat chloride.

We further probed this post hoc sensitivity analysis using the model specified in the trial, MMRM, or mixed model for repeated measures, shown here on slide 10. The dark blue bars represent this pre-specified sweat chloride analysis in all 14 participants. The primary result, as we reported in August, was a mean change of -1 millimole per liter. In the pre-specified secondary analysis, using each treatment period as its own baseline, the mean change was essentially the same, -1.1 millimole per liter. The teal bars represent post hoc analyses showing the impact of removing the three participants with outlying PK. The top teal bar shows the result using study day one as baseline, a mean sweat chloride reduction of 3.8 millimole per liter.

The bottom teal bar shows the result using each treatment period's baseline, which we believe best accounts for observed variability, a mean reduction of 8.6 millimole per liter. We believe that this post hoc analysis provides a less confounded view of the data and shows evidence of biological activity from NBD1 stabilization. On slide 11, we show that the mean trough, or pre-dose exposures of all three components of Trikafta, or ETI, declined on average over the course of the 719 period, while ETI levels were generally stable on average during the placebo period. We mentioned this observation when we first reported the data. The dark blue bars represent the mean changes in ETI levels from left to right, elexacaftor, tezacaftor, and ivacaftor in the placebo period, and the teal bars represent mean change in ETI levels over the 719 period. The three PK outlier participants are not included.

As you can see, ETI concentrations remained relatively stable on average during the placebo period, while they declined by approximately 25%-30% on average over the 719 period. While we could not quantify the potential impact of this finding, this is not what we intended or expected when we designed the trial, and we believe it's possible that lower exposures of some or all of these components could have reduced the incremental effect of adding NBD1. Importantly, this specific four-drug complexity will not be a factor when 451 plus 2222 is studied as a standalone dual combination. Before we describe our emerging biological hypothesis, here on slide 12 is a brief refresher on CFTR and CFTR modulators. CFTR is a multi-domain protein. The most common mutation, F508del, resides in the NBD1 region and creates multiple defects in protein processing, trafficking, and function.