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Sionna Therapeutics PreciSIONCF Key Learnings and Plans to Advance Dual Combination September 14th, 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, including our interpretation of, and hypotheses regarding, the results of the PreciSION CF trial and the impact of potential confounding factors on our interpretation and hypotheses; the potential for NBD1 stabilization to improve CFTR function and produce clinical benefit, including beliefs about biological activity of SION-719 in PreciSION CF and the translatability of preclinical and in vitro assay data to clinical outcomes; the objectives, design, timing, initiation and conduct of a planned Phase 2a proof-of-concept trial of SION-451 + SION-2222; the therapeutic potential, clinical benefits and safety of SION- 451 + SION-2222; the expected timing, scope, costs and benefits of the workforce reduction and other cost-saving measures; our ability to retain the capabilities and personnel needed to advance SION-451 + SION-2222 and operate as a public company; 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 interpretation of the PreciSION CF results and potential confounding factors, and 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 the Company’s operations; the inherent limitations of post hoc analyses, which are exploratory and may not reliably predict future outcomes; the risk that in vitro and preclinical data may not translate to clinical benefit; the risk that results observed with one compound may not be predictive of results with a different compound or combination; risks regarding the initiation, timing, progress, and results of future clinical trials, including the planned Phase 2a trial; and uncertainties about the impact of steps to preserve capital on the Company’s ability to engage in development. Additional risks include 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 (“FDA”) 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 CF 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 most recent Quarterly Report on Form 10-Q and Current Report on Form 8-K, 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 FDA. 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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We have strong conviction in the NBD1 biology, and believe there is compelling rationale to pursue the dual combination 3 In post hoc analysis, removing clear confounders, SION-719 improved mean sweat chloride up to -8.6 mmol/L Post hoc observations provide evidence of NBD1 target engagement & biology 4-drug combination may have limited NBD1 impact due to lower Trikafta exposures and a potential interaction with the potentiator, ivacaftor Combination with Trikafta® may have blunted NBD1 impact We believe SION-451 + SION -2222 has the potential to deliver a compelling new CF treatment option Dual combination advancing to Ph 2a POC ~$268M cash as of 2Q26; 46% workforce reduction and cost saving initiatives expected to extend cash runway into 2H29, supporting execution of dual combo strategy Cash preservation actions taken NBD1 - Nucleotide Binding Domain 1 of CFTR (CF transmembrane conductance regulator) CF – Cystic Fibrosis; Ph – Phase; POC – proof-of-concept Trikafta is a registered trademarks of Vertex Pharmaceuticals Incorporated
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SION-719 PreciSION CF Phase 2a Trial Post Hoc Analysis
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PreciSION CF Phase 2a trial used a randomized, double-blind crossover design to evaluate SION-719 added to background 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 BID – twice a day; SwCl – sweat chloride; PK – pharmacokinetics MMRM – Mixed Model with Repeated Measures Sequence 1 Sequence 2 SION-719 30mg dosed BID 5 Primary Analysis Mean SwCl change from baseline at Day 1, during SION-719 and placebo treatment periods using MMRM Prespecified analysis of mean SwCl change from each treatment period baseline, during SION-719 and placebo periods using MMRM Secondary Analysis 14 participants completed trial We believe period-specific baselines better account for PK & SwCl variability observed in trial
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Multiple dimensions of the PreciSION CF post hoc analysis consistently identified three key potential confounding factors Three participants had no or unusually low SION-719 or Trikafta exposures, consistent with dosing non-adherence PK Outliers Excluding these participants, signals of NBD1 target engagement and biological activity were observed ETI Exposure CFTR Channel Biology SION-719 + ETI showed high CFTR current before stimulation in nonclinical assay Four-drug combination potentially limited response by dysregulating the CFTR channel Lower ETI exposures may have blunted incremental impact of NBD1 1 ETI exposures were lower by an average of ~25-30% during SION-719 treatment 2 3 ETI – elexacaftor/tezacaftor/ivacaftor, the components of Trikafta 6
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The placebo-adjusted sweat chloride outcome was very different than what we expected 7 -40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant SION-719 Treatment Period -40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant Placebo Treatment Period -40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant Total Placebo-Adjusted Secondary SwCl analysis - full data set (N=14) Confounded participants* Confounded participants* Confounded participants* Note: End of placebo-period values were imputed for two participants with missing observations. Participants are ordered within each panel by magnitude of sweat chloride change. Individual SwCl changes calculated from each treatment period baseline *3 participants with PK patterns consistent with dosing non-adherence
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Observation 8 A deep dive into the data identified patterns in 3 participants consistent with dosing non-adherence that may have confounded results No other participants identified with these patterns consistent with dosing non-adherence Study Impact 1 participant with unmeasurable Trikafta and 1 participant with unusually low levels of Trikafta after washout at start of placebo period Believed to have caused direct and confounding placebo SwCl response of -24.0 and -12.5 mmol/L 1 participant with unmeasurable SION-719 at the end of the treatment period Believed to have caused direct and confounding increase in SwCl of +14.5 mmol/L during SION-719 treatment period
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-40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant Placebo Treatment Period Removing 3 confounded participants, the post hoc treatment and placebo data indicate NBD1 stabilization -40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant SION-719 Treatment Period -40 -30 -20 -10 0 10 20 30 40 Mean SwCl Change (mmol/L) Individual Participant Total Placebo-Adjusted Secondary SwCl analysis - excluding 3 confounders (N=11) Individual SwCl changes calculated from each treatment period baseline 9 Note: End of placebo-period values were imputed for two participants with missing observations. Participants are ordered within each panel by magnitude of sweat chloride change.
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10 Post hoc analysis shows up to -8.6 mmol/L mean sweat chloride change, which we believe is evidence of NBD1 activity CONFIDE NTIAL -1.0 -1.1 -3.8* -8.6* All participants (N = 14) Excluding confounded participants (N = 11) LS Mean Placebo-Adjusted SwCl Change (mmol/L) Treatment period baselines Change in SwCl calculated from baseline measured at start of each period Study Day 1 baseline Change in SwCl calculated from baseline measured on Day 1 Primary Analysis Secondary Analysis *Post hoc analysis (p=0.70)
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• ETI exposures were relatively stable during placebo periods but declined during SION-719 treatment • We could not quantify the potential impact of this 4-drug interaction, but it is possible that lower Trikafta exposure may have blunted NBD1 impact • We believe this confounding effect will not be a factor with our dual combination On average, decreased ETI exposures during SION-719 treatment However, we expected a larger treatment effect – this may have been due to lower Trikafta exposures when combined with SION-719 11 96% 70% 97% 77% 101% 75% Placebo ∆ Tx ∆ Placebo ∆ Tx ∆ Placebo ∆ Tx ∆ ELX TEZ IVA Change in mean concentrations of Trikafta (ETI) during placebo and treatment periods Excluding 3 confounded participants (N=11) ELX TEZ IVA Key observations Note: concentrations are trough (pre-dose) levels ELX – elexacaftor; TEZ – tezacaftor; IVA – ivacaftor Tx = treatment period
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CFTR modulators target distinct regions of CFTR, and work in different ways to restore function 12 CFTR STRUCTURE Cell Membrane Potentiator (TMD2) TMD1 ICL4 NBD1 F508del Mutation SION-2222 SION-719 SION-451 TMD1 and ICL4 Correctors help CFTR fold properly, reach the cell surface and remain more stable there by targeting regions around NBD1 NBD1 stabilizers directly target NBD1, where F508del resides 1. We believe stabilizing NBD1 is critical to CFTR folding, trafficking and function Potentiators increase channel opening, enabling greater chloride transport through CFTR 1. Thibodeau 2010 ICL4 – Intracellular Loop 4 of CFTR; TMD – Transmembrane Domain 1 and 2 of CFTR
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PreciSION CF outcome informed an emerging hypothesis regarding CFTR channel behavior when NBD1 is combined with a potentiator 13 Protein Maturation Trafficking Half-life CFHBE stimulated current CFHBE pre-stimulated current SION-451 NBD1 SION-2222 TMD1 ETI SOC SION-719 NBD1 Restored up to wild-type Higher than wild-type Wild-type levels Add-On Dual Combination Note: all data from Sionna conducted nonclinical studies CFHBE – CF Human Bronchial Epithelial primary cells; SOC – standard of care Restored up to wild-type Nonclinical data: Restored up to wild-type Restored up to wild-type Restored up to wild-type Restored up to wild-type Restored up to wild-type Restored up to wild-type
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1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) DMSO ETI CFTR channel activity in CFHBE model: normal and CF cells with ETI 14 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) CFTR channel before stimulation Stimulated CFTR Inhibited CFTR CFTR channel before stimulation Stimulated CFTR Inhibited CFTR Low activity before stimulation Higher stimulated current Normal regulation ETI modulated F508del-CFTR at Emax ETI F508del CFTR Wild-Type Note: F508del-CFTR and wild-type traces shown each represent a single donor with 4 replicates, and are representative of the observed profiles from 6 donors in the same experiment Poorly responsive Strong response to stimulation
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CFTR channel before stimulation Stimulated CFTR Inhibited CFTR 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) DMSO ETI ETI+719 Activity before stimulation Increase in current with stimulation ETI F508del CFTR SION-719+ETI CFTR channel activity in CFHBE model: normal and CF cells with SION-719 (NBD1) + ETI 15 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) CFTR channel before stimulation Stimulated CFTR Inhibited CFTR Low activity before stimulation Normal regulation SION-719 + ETI modulated F508del-CFTR at Emax Wild-TypeStrong response to stimulation Note: F508del-CFTR and wild-type traces shown each represent a single donor with 4 replicates, and are representative of the observed profiles from 6 donors in the same experiment 30mg of ‘719 pre stimulated current is ~50% of Emax
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1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) DMSO 451+2222 ETI ETI+719 CFTR channel before stimulation Stimulated CFTR Inhibited CFTR ETI F508del CFTR SION-719+ETI SION-451+SION-2222 Resembles wild-type CFTR channel activity in CFHBE model: normal and CF cells with SION-451 (NBD1)+ SION-2222 (TMD1) 16 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 0 10 20 30 40 50 60 70 80 Time (s) Ieq (μA/cm2) CFTR channel before stimulation Stimulated CFTR Inhibited CFTR Low activity before stimulation Normal regulation Dual combination modulated F508del-CFTR at Emax Wild-TypeStrong response to stimulation Note: F508del-CFTR and wild-type traces shown each represent a single donor with 4 replicates, and are representative of the observed profiles from 6 donors in the same experiment
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SION-451 Dual Combination Next Steps
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Meaningful opportunity exists for alternative CF treatment options beyond the standard of care 18 1. Konstan, NACFC poster 2022; 2. Zemanick, JCF 2024; 3. Normal sweat chloride <30 mmol/L 4. Alyftrek USPI (March 2026); 5. Trikafta USPI (March 2026); 6. VRTX 2Q26 earnings call; 7. 2025 Wall Street research estimates CNS – central nervous system >2/3rd of patients on SOC do not have normal CFTR function, as measured by sweat chloride1,2,3 High Unmet Need Many patients on SOC experience tolerability challenges like liver side effects or CNS burden4,5 CF is a one-player, ~$13B market today6, expected to grow to ~$15B-17B by 20307 More Options Desired Current SOC are all built on the same mechanisms of action and do not directly stabilize NBD1
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Phase 1 established SION-451 + SION-2222 as our preferred dual combination 19 Trial Design & Conduct • Evaluated safety, tolerability, and PK across multiple 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 • Achieved safety and tolerability objectives • Exceeded PK target at go-forward doses • Combination PK was consistent with respective single agent Phase 1 profiles • SION-451 + SION-2222 identified as preferred combination based on target coverage • Data support advancement of SION-451 + SION-2222 as a potential next-generation dual combination • PreciSION CF learnings are informing next phase of development
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20 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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• Open-label trial in adults with F/F CF treated for 28 days • Assess sweat chloride, safety and PK • Demonstrate first clinical data with Sionna Dual Combination in CF participants • Simple switch from Trikafta • PreciSION CF lessons will be incorporated with respect to dosing adherence and variability Phase 2a Open-Label POC 21 AscenSION CF proof-of-concept trial of SION-451 + SION-2222 expected to initiate in 1Q27 SAD – single ascending dose; MAD – multiple ascending dose; HV – healthy volunteer F/F – homozygous for F508del mutation PROPRIETARY DUAL COMBINATION Completed SION-2222 (galicaftor) TMD1 SION-451 NBD1 Phase 1 SAD/MAD in HVs Phase 1 Combo in HVs Phase 2a POC AscenSION CF Dual Combo Open-label Phase 2b AscenSION CF 2 Dual Combo Dose-Ranging
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22 Dual combination offers a differentiated two-drug approach to current triple-combination therapies 1. VRTX 2Q26 earnings call SION-451 NBD1 SION-2222 TMD1 Supported by favorable tolerability and PK from Ph 1 trial, SION-451 + SION-2222 is advancing to AscenSION CF Ph 2a to evaluate preliminary efficacy and safety in CF participants Proprietary approach anchored by novel NBD1 mechanism of action Designed to target meaningful CFTR benefit in a two-drug regimen compared to the triple- regimen standard Ph 2a POC designed as an efficient study to evaluate the potential profile of this combination ~$13B1 market seeking alternative treatment options
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Q&A