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Sionna Therapeutics Topline Data from Two NBD1 Stabilizer Programs August 10, 2026
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2 Disclaimers and forward-looking statements This presentation contains forward-looking statements of Sionna Therapeutics, Inc. (“Sionna”, “the Company”, “we”, “us”, or “our”) that involve substantial risks and uncertainties. All statements other than historical factual information are forward-looking statements, including without limitation express or implied statements regarding our goal of transforming the treatment paradigm for CF; the initiation, timing, progress and results of our research and development programs, preclinical studies, and clinical trials and studies; our ability to replicate positive results from earlier preclinical studies or clinical trials conducted by us or third parties in current or future clinical trials; our ability to develop and advance our current and future product candidates and programs; our ability to demonstrate that our product candidates are safe and effective for their proposed indication and our expectations around their beneficial characteristics and therapeutic effects; our ability to advance our current and future product candidates through applicable regulatory approval processes; the implementation of our business model and strategic plans; our estimates regarding the market opportunity of our product candidates; our ability to rely on third-party manufacturers and successfully manufacture our product candidates for preclinical use, for clinical trials and on a larger scale for commercial use, if approved; our ability to maintain, expand and protect our intellectual property; our ability to enter into future license agreements and collaborations; general economic, industry, and market conditions, including rising interest rates and inflation; our ability to attract and retain key scientific and management personnel; our ability to compete effectively with existing competitors and new market entrants; and our expectations regarding our pipeline, operating plan, use of capital and capital requirements, expenses and other financial results, including any cash runway projections. In some cases, you can identify forward-looking statements because they contain words such as “may,” “will,” “shall,” “should,” “expects,” “plans,” “anticipates,” “could,” “intends,” “target,” “projects,” “contemplates,” “believes,” “estimates,” “predicts,” “potential,” or “continue” or the negative of these words or other similar terms or expressions that concern our expectations, strategy, plans or intentions, although not all forward-looking statements are accompanied by such words. Forward-looking statements are based on assumptions and assessments made by our management in light of their experience and perceptions of historical trends, current conditions, expected future developments and other factors they believe to be appropriate, and speak only as of the date of this presentation. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or other events to be materially different from any future results, performance or other events expressed or implied by the forward-looking statements. Given these uncertainties, you should not place undue reliance on forward-looking statements. Our actual future results, performance or other events may be materially different from what we expect. Except as required by law, we assume no obligation to update these forward-looking statements, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. Factors that could cause actual results to differ from those predicted in our forward-looking statements include, among other things: uncertainties inherent in the development of product candidates, including the results of the PreciSION CF trial, potential confounding factors, and once studied further, what the data may mean for next steps for the SION-451 dual combination program, the CFHBE translational framework, future development of the Company’s pipeline, and operations; uncertainties about the impact of steps to preserve capital on the Company’s ability to engage in development; the initiation, timing, progress, and results of future clinical trials; our ability to replicate positive results from earlier preclinical studies or clinical trials conducted by us or third parties in any future clinical trials; our ability to demonstrate that our NBD1 stabilizers, complementary CFTR modulators, and potential future product candidates are safe and effective for their proposed indications and our expectations around their beneficial characteristics and therapeutic effects; our ability to advance our current programs and any potential future product candidates through applicable regulatory approval processes, including timing of U.S. Food and Drug Administration approval, if any, of our current and any future product candidates; our estimates of the number of patients that we will enroll and our ability to initiate, recruit and enroll patients in and conduct and successfully complete our clinical trials at the pace we project; the implementation of our business model and strategic plans; our ability to rely on third-party manufacturers; the size and growth potential of the cystic fibrosis market for our programs and our ability to serve those markets; our ability to realize the benefits of collaborations for the development and commercialization of our programs or any other potential future product candidates; our ability to maintain, expand and protect our intellectual property; developments relating to our competitors and our industry; existing regulations and regulatory developments in the United States and other jurisdictions; general economic, industry, and market conditions, including potential tariffs implications, supply chain disruptions, rising interest rates and inflation; our ability to attract, hire, and retain our key personnel and additional qualified personnel; and those risks and uncertainties identified in our filings with the Securities and Exchange Commission (the “SEC”), including our Annual Report on Form 10-K, filed on March 2, 2026, as well as any subsequent filings with the SEC. These risks are not exhaustive. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. Market data and industry information used throughout this presentation are based on management’s knowledge of the industry and the good faith estimates of management. We also relied, to the extent available, upon management’s review of independent industry surveys and publications and other publicly available information prepared by a number of third-party sources. All of the market data and industry information used in this presentation involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Although we believe that these sources are reliable as of their respective dates, we cannot guarantee the accuracy or completeness of this information, and we have not independently verified this information. Projections, assumptions and estimates of our future performance and the future performance of the industry in which we operate are necessarily subject to a high degree of uncertainty and risk due to a variety of factors. These and other factors could cause results to differ materially from those expressed in our estimates and beliefs and in the estimates prepared by independent parties. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. This presentation discusses product candidates that are investigational only and have not yet been approved for marketing by the U.S. Food and Drug Administration. No representation is made as to the safety or effectiveness of these product candidates for the use for which such product candidates are being studied.
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Key takeaways from today’s announcement 3 The trial demonstrated a -1.0 mmol/L mean placebo-adjusted sweat chloride change (p = 0.7) when SION-719 was added to Trikafta® We are not advancing development of SION-719 as an add-on to SOC We will continue to analyze the results of PreciSION CF, including potential confounding factors PreciSION CF Phase 2a did not meet key activity endpoint The Phase 1 dual combination trial achieved the safety, tolerability, and PK objectives that we had defined prior to the Phase 2a PreciSION CF results Continued evaluation of the SION-719 data will inform the next steps for the SION-451 clinical program SION-451 dual combination program CF – Cystic Fibrosis; SOC – standard of care PK – pharmacokinetics Trikafta is a registered trademark of Vertex Pharmaceuticals Incorporated
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4 Agenda SION-719 PreciSION CF Phase 2a Proof-of-Concept Trial Topline Results SION-451 Phase 1 Healthy Volunteer Dual Combination Trial Topline Results Closing Remarks Q&A 1 2 3 4
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PreciSION CF Phase 2a proof-of-concept trial evaluated SION-719 when added to Trikafta Phase 2a Endpoints Primary: Safety, Tolerability Secondary: Sweat Chloride, PK Trial powered for ≥10 mmol/L SwCl change Trial Population Adult CF participants homozygous for F508del on stable dose of physician- prescribed Trikafta Screening 28 Day Trikafta Run-In 14 Day SION-719 + Trikafta Placebo + Trikafta 14 Day Safety Follow-up 14 Day Placebo + Trikafta SION-719 + Trikafta 14 Day SION-719 Washout 28 Day n = 8 n = 6 Primary analysis plan • Primary sweat chloride analysis compared patient change from baseline during SION-719 and placebo treatment periods using an MMRM method • Safety analysis was a description of adverse events reported by each treatment group within each period BID – twice a day; SwCl – sweat chloride MMRM – Mixed Model with Repeated Measures Sequence 1 Sequence 2 SION-719 30mg dosed BID 5
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6 Summary of baseline and demographic characteristics SD – standard deviation; BMI – body mass index Overall N=15 Age, years, mean (SD) 35.1 (7.9) Sex [n (%)] Female 7 (46.7) Male 8 (53.3) Ethnicity [n (%)] Non- Hispanic or Latino 15 (100) Race White 15 (100) BMI (kg/m2) [mean (SD)] 25.5 (3.3) Sweat Chloride (mmol/L) [mean (SD)] 56.5 (10.5) PreciSION CF enrolled adult CF participants homozygous for F508del who were stable on Trikaftafor at least 3 months before screening
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7 PreciSION CF Phase 2a proof-of-concept trial results Mean placebo-adjusted sweat chloride change of -1.0 mmol/L (p = 0.7) when patients were taking a 30mg BID dose of SION-719 on background of Trikafta Potential trial confounders were observed, including SwCl variability, and differences in Trikafta exposure levels between the SION-719 and placebo periods SION-719 was generally well tolerated when added to Trikafta for 14 days; no meaningful trends in AEs SION-719 exposure in the study was consistent with single agent PK Mean Trikafta exposures were consistent with published data; however, there were trends of lower Trikafta exposure in the SION-719 treated periods, which we believe were driven by individual variability Key Activity Endpoint Safety & Tolerability PK Exposure As a result of today’s data, we are not advancing SION-719 as an add-on to SOC We continue to evaluate the impact of potential confounders on the interpretation of the trial data AE – adverse event
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8 Placebo SION-719 30mg BID Sequence 1 Sequence 2 Overall Sequence 1 Sequence 2 Overall Trial Participants (n) N=6 N=8 N=14 N=7* N=8 N=15* Total number of TEAEs 3 20 23 8 14 22 Participants with any TEAE, n (%) 3 (50%) 4 (50%) 7 (50%) 5 (71%) 7 (88%) 12 (80%) Mild (Grade 1) 2 (33%) 2 (25%) 4 (29%) 3 (43%) 5 (63%) 8 (53%) Moderate (Grade 2) 1 (17%) 2 (25%) 3 (21%) 2 (29%) 1 (13%) 3 (20%) Severe (Grade 3) - - - - 1 (13%) 1 (7%) Leading to treatment discontinuation - - - - - - Serious TEAEs, n (%) - - - - - - Participants with liver function test associated TEAE 1 (17%) 1 (13%) 2 (14%) - 2 (25%) 2 (13%) TEAE – treatment-emergent adverse event; SAE – serious adverse event LFT – liver function test Sequence 1= 719placebo; Sequence 2= placebo719 *includes 1 participant who discontinued for reasons not related to treatment • Most TEAEs were mild to moderate, and no SAEs • No meaningful trends in LFTs. One grade 3 LFT observed at end of washout period pre-dosing, which resolved over the course of SION-719 treatment • 1 participant discontinued, unrelated to an adverse event SION-719 was generally well tolerated when added to Trikafta with most TEAEs mild to moderate
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9 Agenda SION-719 PreciSION CF Phase 2a Proof-of-Concept Trial Topline Results SION-451 Phase 1 Healthy Volunteer Dual Combination Trial Topline Results Closing Remarks Q&A 1 2 3 4
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Phase 1 clinical evaluation of SION-451 anchored dual combinations 10 Trial Design & Conduct • Evaluated the safety, tolerability, and PK profiles of different dose combinations of SION-451 + SION-2222 and SION-451 + SION-109 in healthy volunteers • 3:1 randomized, double-blind, placebo-controlled cohorts • All cohorts dosed for 14 days • Cohorts dosed in fasted conditions, except 1 cohort in each dual combination administered with food SION-451 NBD1 SION-2222 TMD1 SION-451 NBD1 SION-109 ICL4 60 total participants dosed (5 cohorts) 60 total participants dosed (5 cohorts) Trial Outcome • Trial achieved its safety, tolerability, and PK objectives, including target exposures defined prior to the Phase 2a PreciSION CF results • SION-451 + SION-2222 identified as preferred combination based on target coverage. PK of this combination was consistent with single agent Phase 1 data • Actively assessing results of PreciSION CF, including our translational framework, to help characterize the potential profile of the SION-451 + SION-2222 dual combination NBD1 – Nucleotide Binding Domain 1 of CFTR TMD – Transmembrane Domain 1 and 2 of CFTR; ICL4 – Intracellular Loop 4 of CFTR
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11 SION-451 BID + SION-2222 QD demonstrated a favorable tolerability profile SION-451 BID + SION-2222 QD *preferred regimen All cohorts generally well tolerated All TEAEs were mild to moderate with no SAEs and no TEAEs associated with elevated LFTs Safety profile consistent with prior single agent clinical trials of SION-451 BID and SION-2222 QD One participant discontinued due to moderate rash SION-451 BID + SION-2222 BID Most TEAEs were mild to moderate with no SAEs Two participants discontinued due to elevated LFTs and flu-like symptoms; both cases were confounded3 Placebo SION-451 BID + SION-2222 QD SION-451 BID + SION-2222 BID Total Trial Participants (n) (n=15) 3 cohorts (n=27) 2 cohorts (n=18) (n=60) Participants with any TEAE, n (%) 5 (33) 19 (70) 10 (56) 34 (57) Mild (Grade 1) 5 (33) 15 (56) 10 (56) 30 (50) Moderate (Grade 2) 1 (7) 10 (37) 5 (28) 16 (27) Severe (Grade 3)1 - - 2 (11) 2 (3) Leading to treatment discontinuation - 1 (4) 2 (11) 3 (5) Serious TEAEs, n (%) - - - - Most frequent TEAEs (≥3 participants), n (%) Headache 4 (27) 4 (15) 3 (17) 11 (18) Diarrhea 1 (7) 6 (22) 4 (22) 11 (18) Fever - - 4 (22) 4 (7) Abdominal Pain - 2 (7) 1 (6) 3 (5) Elevated Liver Associated Enzymes2 - - 3 (17) 3 (5) Intravenous Site Phlebitis - 2 (7) 1 (6) 3 (5) 2. Elevated liver associated enzymes included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase 3. Two participants dosed with SION-2222 BID who discontinued were confounded by other factors, including potential infection QD – once a day 1. Grade 3 TEAEs of ALT increased, AST increased, GGT increased, lymphocyte count decreased, neutrophil count decreased
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12 Agenda SION-719 PreciSION CF Phase 2a Proof-of-Concept Trial Topline Results SION-451 Phase 1 Healthy Volunteer Dual Combination Trial Topline Results Closing Remarks Q&A 1 2 3 4
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13 Next steps for Sionna following today’s clinical results NEXT STEPS Sionna does not plan to advance SION-719 as an add-on to SOC We will continue to analyze the results of the SION-719 PreciSION CF study, and assess implications for the SION-451 dual combination program CASH CONSIDERATIONS ~$268 million in cash and cash equivalents as of 2Q26 Plan to take action to preserve capital while evaluating next steps
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14 Agenda SION-719 PreciSION CF Phase 2a Proof-of-Concept Trial Topline Results SION-451 Phase 1 Healthy Volunteer Dual Combination Trial Topline Results Closing Remarks Q&A 1 2 3 4