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Sionna Therapeutics On a Mission to Revolutionize the Cystic Fibrosis Treatment Paradigm January 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 statements regarding our goal of transforming the treatment paradigm for CF and providing clinically meaningful benefit to patients, including the potential for wild-type CFTR function and half-life; the initiation, timing, progress and results of our research and development programs, preclinical studies, and clinical trials and studies, including the expected timing of topline data from our Phase 1 healthy volunteer combination trial and the Phase 2a proof-of-concept trial; 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 our cash runway projection. 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: the initiation, timing, progress, and results of our planned and future clinical trials; 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 demonstrate that our NBD1 stabilizers, complementary CFTR modulators, and any 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, including our Quarterly Report on Form 10-Q, filed on November 5, 2025, 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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Sionna Overview
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Leadership with track record capable of disrupting the CF market Leadership Board of Directors Paul Clancy Board Chair Prior CFO Alexion, Biogen Bruce Booth, D. Phil. Director Partner, Atlas Venture Mike Cloonan Director CEO, Sionna Edd Flemming, M.D. Director EVP, Enavate Sciences Lucian Iancovici, M.D. Director Partner, TPG Growth Josh Resnick, M.D. Director Partner, RA Capital Peter Thompson, M.D. Director Partner, Orbimed Laurie Stelzer Director Prior CFO Kailera, Mirati, Arena Jo Viney, Ph.D. Director CEO, Seismic Therapeutic Marcie Ruddy, M.D. Director CMO, Tectonic Therapeutic CF – Cystic Fibrosis Chief Executive Officer Mike Cloonan Chief Medical Officer Charlotte McKee, M.D. Chief Financial Officer Elena Ridloff, C.F.A. Chief Business Officer Caroline Stark Beer, MBA Chief Legal Officer Jen Fitzpatrick Chief People Officer Vanya Sagar Co-Founder & SVP Discovery Research Greg Hurlbut, Ph.D. Co-Founder & SVP Medicinal Chemistry Mark Munson, Ph.D. 4
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Sionna leverages over 15 years of pioneering CFTR research and development to advance next-generation of CF therapies 2009 2019 2022 2024 2025 CF program spun out of Sanofi by Sionna co-founders and funded by RA Capital, TPG, and the CFF NBD1 and CFTR research started by Sionna co-founders at Genzyme and Sanofi, supported by CFF Sionna Therapeutics emerged from stealth with $150M in funding Raised $182M Series C, initiated two first-in-class NBD1 Ph 1 trials, in-licensed AbbVie assets to expand CF pipeline Completed $219M IPO, and advanced two NBD1s to next stages of development following two successful Ph 1 studies NBD1 - Nucleotide Binding Domain 1 of CFTR; CFTR - CF transmembrane conductance regulator; Ph – Phase 5
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FRANCHISE DRIVES STRATEGIC OPTIONALITY PREDICTIVE ASSAY / BIOMARKERS* NBD1, A CRITICAL CF TARGET Sionna’s novel approach focused on stabilizing NBD1 has the potential to revolutionize the current CF treatment paradigm HIGH UNMET NEED IN LARGE MARKET Despite current treatments, >2/3rd of patients do not have normal CFTR function1 Today’s market is >$12B2, expected to be $15B-$17B by 20303 We believe NBD1 has the potential to deliver full CFTR function, and none of the approved CFTR modulators directly stabilize NBD1 Industry standard CFHBE assay and sweat chloride biomarker have been highly predictive of clinical outcomes for approved CFTR modulators Robust clinical stage pipeline of NBD1 stabilizers and complementary modulators provides multiple potential paths to transform the standard of care for CF patients 1. Konstan, NACFC poster 2022; 2. VRTX 3Q25 earnings call; 3. 2025 Wall Street research estimates; *Source: Preclinical assays conducted by Sionna; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ; CFHBE – CF Human Bronchial Epithelial primary cells 6
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>2/3rd of patients on Trikafta® do not have normal CFTR function, as measured by sweat chloride4,5 ~106K patients with CF across 94 countries1 ~90% of people with CF carry the F508del mutation2, which is Sionna’s target population Predicted median survival is 65 years for a patient born in the U.S. between 2020 and 20243 CF is an established rare, progressive and life-threatening genetic disease that can cause debilitating multi-system complications 1. CFF estimates 2024, 2024 CFF Registry data, 2022 ECFS Registry; 2. Taylor-Cousar 2019 3. 2024 CFF Registry data; 4. Konstan, NACFC poster 2022; 5. Normal sweat chloride <30 mmol/L Trikafta is a registered trademark of Vertex Pharmaceuticals Incorporated Manifestations of Cystic Fibrosis 7
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Cell Membrane TMD2 TMD1 ICL4 NBD1 NBD2 F508del Mutation SION-2222 SION-2851 SION-109 SION-719 SION-451 SION-3067 We believe stabilizing NBD1 is central to unlocking meaningful improvements in clinical outcomes for CF patients CFTR Structure ~90% of people with CF have a F508del mutation; F508del resides within the NBD1 domain of CFTR F508del severely destabilizes CFTR, preventing its normal folding, trafficking, and function We believe stabilizing NBD1 is the key to normalizing CFTR function None of the approved CFTR modulators directly stabilize NBD1 The Importance of NBD1 TMD – Transmembrane Domain 1 and 2 of CFTR; ICL4 – Intracellular Loop 4 of CFTR 8
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PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 1 COMBO PHASE 2 UPCOMING MILESTONES Complete Ph 1 HV dual combo, TLD mid-26 Complete Ph 1 HV dual combo, TLD mid-26 PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 2 UPCOMING MILESTONES Complete Ph 2a POC, TLD mid-26 SION-719 NBD1 Galicaftor* SION-2222 TMD1 SION-451 NBD1 SION-109 ICL4 SION-451 NBD1 ADD-ON TO STANDARD OF CARE NBD1 Stabilizer + SOC PROPRIETARY DUAL COMBINATIONS NBD1 Stabilizer + Complementary Modulator PROGRAM / MECHANISM PRECLINICAL PHASE 1 PHASE 2 SION-2851 TMD1 Navocaftor* SION-3067 Potentiator Lifecycle Development Sionna has a robust and differentiated pipeline, with several near-term clinical milestones *Licensed compounds from AbbVie; Clinical trials conducted by AbbVie; Galicaftor and Navocaftor completed Ph 2 combination trials; POC – Proof of concept; SOC – standard of care; HV – healthy volunteer; TLD – Topline Data 9
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Our vision is to build a CF franchise anchored by our NBD1 stabilizers to deliver meaningful clinical benefit to CF patients SION-719 NBD1 Trikafta SOC Add-on to SOC for POC SION-719 + SOC Both paths offer attractive commercial opportunities; the Dual Combination path is prioritized for its potential to deliver the greatest value for both patients and Sionna Next Clinical Step Rationale for NBD1 Selection SION-719 has greater potency SION-719 PreciSION CF Ph 2a POC trial ongoing SION-451 NBD1 SION-2222 TMD1 SION-451 NBD1 SION-109 ICL4 Dual Combination Development SION-451 + ICL4 / TMD1 SION-451 achieved higher exposure SION-451 Ph 1 HV combination trial ongoing Prioritized Development Path 10
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Meaningful progress in 2025 has strengthened our foundation, paving the way for 2026 execution Clinical Execution Near-Term Milestones Scientific Progress Strong Financial Position Positive Ph 1 data from single agent NBD1 stabilizers SION-719 and SION-451 Completed DDI study supporting initiation of the SION-719 Ph 2a POC trial Ongoing Ph 2a PreciSION CF POC trial of SION-719 added to SOC, on-track for data mid-2026 Ongoing Ph 1 HV trial of SION-451 in dual combinations, on-track for data mid-2026 Presented new preclinical data showing SION-719 and SION-451 increased F508del-CFTR half-life up to wild-type levels, further underscoring NBD1 potential Cash position of $325.0 million as of 3Q25 Runway into 2028 DDI – Drug-drug interaction 11
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Our approach leverages the clinically predictive CFHBE model, using 20% human serum, designed to more closely simulate the in vivo environment We successfully validated our model by replicating published clinical results In addition to positive outcomes, our model has successfully predicted negative clinical trial outcomes Assay expertise has been honed with over a decade of experience by our team Sionna’s translational CFHBE model is shaped by over a decade of expertise and critical to our strategy supporting NBD1’s differentiation FEV- Forced Expiratory Volume, Gating mutation - G551D CFTR, ELX - elexacaftor, IVA - ivacaftor, LUM - lumacaftor, TEZ - tezacaftor, Trikafta - ELX/TEZ/IVA. Source: Preclinical assays conducted by Sionna; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ 12
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NBD1 Stabilizers: SION-719 & SION-451
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Mechanism of Action NBD1 Stabilizers Rationale and Enthusiasm for Advancement In Phase 1 single agent SAD/MAD HV trials, both SION-719 and SION-451 exceeded desired PK targets o SION-719 selected as add-on to SOC NBD1 based on high potency at low doses o SION-451 selected as NBD1 anchor in dual combinations based on high overall exposures Status Phase 1 SAD, MAD, and FE/BE completed for both compounds SION-719 PreciSION CF Phase 2a POC in CF patients is ongoing SION-451 Phase 1 HV dual combination trial with SION-2222 (galicaftor) and SION-109 is ongoing Key Upcoming Milestones Topline data from ongoing SION-719 Phase 2a POC trial in CF patients expected mid-26 Topline data from ongoing SION-451 Phase 1 HV dual combination trial expected mid-26 Use Case SION-719 as add-on to SOC and SION-451 as anchor to proprietary dual combination Target the ~90% of the CF population that carry the F508del mutation SION-719 and SION-451: novel NBD1 stabilizers advancing to next phase of development PK – pharmacokinetic; SAD – single ascending dose; MAD – multiple ascending dose; FE – Food Effect; BE – BioEquivalence 14
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SION-719 and SION-451: single agent SAD/MAD Phase 1 trial summaries Single agent SAD/MAD Phase 1 trials of SION-451 and SION-719 • Evaluated the safety, tolerability, and PK profiles of single and multiple ascending doses of SION-719 and SION-451 in healthy volunteers • 3:1 randomized, double-blind, placebo-controlled studies in Australia • SAD/MAD parts dosed as oral suspension (fasted unless noted); MAD dosing duration of 10 days • FE/BE Part C evaluated the effect of food on PK and bioequivalence of a tablet formulation compared to oral suspension SION-451 • 110 total subjects dosed: • SAD: 25mg (fed), 75mg (fasted & fed), 150mg, 300mg, 450mg • MAD (BID): 25mg (fed), 75mg, 150mg, 225mg, 300mg • FE/BE Part C: doses in add-on to SOC and dual combo ranges SION-719 • 100 total subjects dosed: • SAD: 20mg (fasted & fed), 40mg, 80mg, 160mg • MAD (BID): 20mg, 40mg, 80mg, 120mg, 160mg • FE/BE Part C: doses in add-on to SOC and dual combo ranges BID – twice a day 15
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SION-719 exceeded target exposures in single agent Phase 1, making it an attractive candidate as add-on to SOC given high potency at lower doses MAD PK Summary Day 10 Through 36 Hours Post-administration PK observations in the SAD portion of the trial were generally consistent with the MAD findings shown Add-on target coverage at all doses studied; dual combination coverage at ≥40mg BID Part C data support use of the tablet in future studies and indicate SION-719 can be dosed in fed or fasted state 0.1 1.0 10.0 100.0 1000.0 0 6 12 18 24 30 36 Mean SION-719 Concentration (ng/mL) Log scale Time (hrs) 20mg BID 40 mg BID 80mg BID 120mg BID 160 mg BID ‘Dual Combo’ Cave target for clinically meaningful benefit ‘Add-on’ Cave target for clinically meaningful benefit Each solid line shows mean concentration data from a dosing cohort on Day 10 High potency and synergy with SOC support lower dose SION-719 for Phase 2a POC trial 16
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SION-719 single agent SAD/MAD Phase 1 data suggest favorable tolerability profile Placebo BID 20 mg BID 40 mg BID 80 mg BID 120 mg BID 160 mg BID MAD Total Study Participants (n)* (n=10) (n=6) (n=6) (n=6) (n=6) (n=6) (n=40) Any TEAE, n (%) 4 (40) 2 (33) 4 (67) 6 (100) 5 (83) 3 (50) 24 (60) Mild (Grade 1) 3 (30) 2 (33) 3 (50) 5 (83) 2 (33) 3 (50) 18 (45) Moderate (Grade 2) 1 (10) - 2 (33) 1 (17) 3 (50) 1 (17) 8 (20) Severe (Grade 3) - - - - - - - Life-threatening (Grade 4) - - - - - - - Leading to treatment discontinuation - - - - - - - Serious TEAEs, n (%) - - - - - - - Most frequent TEAEs (≥2 subjects), n (%) Headache - - 4 (67) 1 (17) 2 (33) 2 (33) 9 (23) Diarrhea 1 (10) 1 (17) - - - 2 (33) 4 (10) Nausea 1 (10) - 1 (17) - - 1 (17) 3 (8) Catheter site phlebitis - - - - 2 (33) - 2 (5) Pruritus 1 (10) - - - - 1 (17) 2 (5) * Safety Population; includes participants who received all or part of at least 1 dose of SION-719 or placebo; SAE – Serious adverse event; TEAE – Treatment emergent adverse event after first dose of drug; LFT – liver function test; ECG – electrocardiogram SION-719 MAD Safety Summary SION-719 SAD, MAD, and FE/BE Safety Highlights • No SAEs; Most TEAEs were mild to moderate (Grade 1 or Grade 2) • No TEAEs led to discontinuation of drug and no dose-limiting TEAEs observed • No TEAEs related to LFTs in treated subjects • No clinically meaningful trends in other safety parameters, vital signs or ECG parameters 17
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0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 Mean CFHBE CFTR-dependent current compared to ETI at its Emax ELX/TEZ/IVA VX440/TEZ/IVA, VX152/TEZ/IVA SION-2222 + SION-3067 TEZ/IVA LUM/IVA IVA F/F IVA G551D F508del homozygous LUM G551D/F508del Minimum target for clinically meaningful improvement to SOC SION-719’s potency at low doses potentially enables a differentiated profile when added to SOC Wild-type range is the average FSK response +/- standard error of the mean across a panel of 8 non-CFHBE primary cell donors Potential of SION-719 as an add-on to SOC* Phase 1 PK data indicate potential for clinically meaningful benefit, including to wild-type levels, as add-on to SOC based on CFHBE target zone Minimum CFHBE target represents at least 10 mmol/L SwCl and ~3 ppFEV1 improvement Wild-type levels of CFTR function *Source: Preclinical assays conducted by Sionna and SION-719 Phase 1 PK; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ Gating mutation – G551D CFTR; ELX – elexacaftor; IVA – ivacaftor; LUM – lumacaftor; TEZ – tezacaftor; Trikafta – ELX/TEZ/IVA; SwCl – Sweat Chloride; ppFEV - Percent Predicted Forced Expiratory Volume SION-719 + ELX/TEZ/IVA Potential zone based on ‘719 clinical exposures 18
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SION-451 is our preferred anchor for dual combinations given exposures achieved in target concentration zones in single agent Phase 1 PK observations in the SAD portion of the trial were generally consistent with the MAD findings shown 0.1 1.0 10.0 100.0 1000.0 10000.0 0 6 12 18 24 30 36 Mean SION-451 Concentration (ng/mL) Log scale Time (hrs) 25mg BID Fed 75mg BID 150mg BID 225mg BID 300mg BID ‘Dual Combo’ Cave target for clinically meaningful benefit ‘Add-on’ Cave target for clinically meaningful benefit Each solid line shows mean concentration data from a dosing cohort on Day 10 MAD PK Summary Day 10 Through 36 Hours Post-administration Dual combination target coverage at ≥75 mg BID; add-on target coverage at all doses studied Part C data support use of the tablet in future studies and indicate SION-451 can be dosed in fed or fasted state High exposures support evaluating SION-451 upper dose range in Ph 1 HV dual combination 19
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SION-451 single agent SAD/MAD Phase 1 data suggest favorable tolerability profile Placebo BID 25 mg BID 75 mg BID 150 mg BID 225 mg BID 300 mg BID MAD Total Study Participants (n)* (n=9) (n=6) (n=5) (n=6) (n=6) (n=6) (n=38) Any TEAE, n (%) 5 (56) 2 (33) 3 (60) 3 (50) 4 (67) 2 (33) 19 (50) Mild (Grade 1) 4 (44) 2 (33) 2 (40) 1 (17) 4 (67) - 13 (34) Moderate (Grade 2) 1 (11) - 1 (20) 1 (17) - 2 (33) 5 (13) Severe (Grade 3) - - - 1 (17) - - 1 (3) Life-threatening (Grade 4) - - - - - - - Leading to treatment discontinuation - - - - - - - Serious TEAEs, n (%) - - - - - - - Most frequent TEAEs (≥2 subjects), n (%) Headache 3 (33) 1 (17) - - 2 (33) 1 (17) 7 (18) Influenza - - - 2 (33) - - 2 (5) Upper Respiratory Tract Infection 1 (11) - - 1 (17) - - 2 (5) * Safety Population; includes participants who received all or part of at least 1 dose of SION-451 or placebo; 1. Subject was in isolated dose cohort of SION-451 (150mg BID) that was impacted by an outbreak of respiratory infection • No SAEs; Most TEAEs were mild to moderate (Grade 1 or Grade 2) • No TEAEs led to discontinuation of drug and no dose-limiting TEAEs observed • 1 Grade 1 TEAE related to LFTs observed in a treated subject who tested positive for influenza 1; no TEAEs related to LFTs in other cohorts • Same subject had transient Grade 3 neutropenia at same time as influenza • No clinically meaningful trends in other safety parameters, vital signs or ECG parameters SION-451 MAD Safety Summary SION-451 SAD, MAD, and FE/BE Safety Highlights 20
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0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 SION-451 in a dual combination has the potential to provide a superior treatment option for people living with CF *Source: Preclinical assays conducted by Sionna and SION-451, SION-2222 and SION-109 Phase 1 PK; results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ Mean CFHBE CFTR-dependent current compared to ETI at its Emax ELX/TEZ/IVA VX440/TEZ/IVA, VX152/TEZ/IVA SION-2222 + SION-3067 TEZ/IVA LUM/IVA IVA F/F IVA G551D F508del homozygous LUM G551D/F508del Minimum target for clinically meaningful improvement to SOC Wild-type range is the average FSK response +/- standard error of the mean across a panel of 8 non-CFHBE primary cell donors Wild-type levels of CFTR function Potential of SION-451 in dual combination* SION-451 + SION-2222 SION-451 + SION-109 Potential zone based on ‘451 clinical exposuresPotential zone based on ‘451 clinical exposures Phase 1 PK data indicate potential for clinically meaningful benefit, including to wild-type levels, in a dual combination based on CFHBE target zone Minimum CFHBE target represents at least 10 mmol/L SwCl and ~3 ppFEV1 improvement 21
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Metabolic pulse-chase analysis studies show NBD1 stabilizers SION-719 and SION-451 increased the half-life of mature F508del- CFTR to levels seen with wild-type CFTR, adding to the growing body of evidence supporting the differentiation of NBD1 New preclinical data show NBD1 stabilizers restored CFTR half-life up to wild-type levels Preclinical studies run by Sionna; Hurlbut, NACFC 2025 poster Our NBD1 stabilizers have the potential to restore both CFTR half-life and CFTR function 22
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Lead Complementary Programs: Galicaftor (SION-2222) & SION-109
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Galicaftor (SION-2222): TMD1-directed CFTR corrector is currently being evaluated in combination with NBD1 stabilizer SION-451 1. Indirect cross-trial comparison; no head-to-head studies have been conducted 2. ClinicalTrials.gov (June 2023) Mechanism of Action TMD1-directed CFTR corrector Rationale and Enthusiasm for Advancement Galicaftor (SION-2222) synergized with NBD1-directed stabilizers in CFHBE assay Phase 2 study M19-530 demonstrated sweat chloride and ppFEV1 outcomes in combination with navocaftor (SION-3067, CFTR potentiator) comparable to approved duals (Symdeko and Orkambi)1 , based on indirect cross-trial comparison Status Phase 2 trials evaluating galicaftor and navocaftor completed2 Phase 1 healthy volunteer dual combination trial with SION-451 is ongoing Key Upcoming Milestones Topline data from Phase 1 healthy volunteer dual combination trial with SION-451 expected mid-26 Use Case Part of a Sionna proprietary dual combination Target the ~90% of the CF population that carry the F508del mutation 24
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Clinical activity similar to Symdeko† observed in phase 2 combination of galicaftor (SION-2222)+ navocaftor (SION-3067) Ph 2 M19-530 trial1 in CF patients homozygous for F508del mutation: • Galicaftor/navocaftor dual combination increased pulmonary function in CF patients • Galicaftor/navocaftor dual combination showed clinical activity at 200 mg QD/150 mg QD and 300 mg QD/150 mg QD doses studied • Improved ppFEV1 and reduced SwCl concentration at 28 days for 200mg and 300mg doses of galicaftor – responses comparable to approved dual combinations Symdeko2† and Orkambi3† 1. Conducted by AbbVie; 2. Symdeko USPI (Aug 2023); 3. Orkambi USPI (Aug 2023); Source: ClinicalTrials.gov (June 2023), galicaftor (ABBV-2222) Investigator Brochure (ed 5), 2022, ClinicalTrials.gov (2018) † indirect cross-trial comparison and as predicted based on our CFHBE model; QD – once daily Data presented as LS mean ± standard error. * p < 0.05; # p < 0.001. N is the number of observations at day 29. Navocaftor Galicaftor Dose (mg) 25
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SION-109: ICL4-directed CFTR corrector is currently being evaluated in combination with NBD1 stabilizer SION-451 Mechanism of Action ICL4-directed CFTR corrector Rationale and Enthusiasm for Advancement SION-109 synergized with NBD1-directed stabilizers in the CFHBE assay ‒ Promising profile and tractable predicted target clinical dose ‒ Dual combination with either of our NBD1 stabilizers resulted in wild-type levels of CFTR function in the CFHBE assay Status Phase 1 healthy volunteer dual combination trial with SION-451 is ongoing Key Upcoming Milestones Topline data from Phase 1 healthy volunteer dual combination trial with SION-451 expected mid-26 Use Case Part of a Sionna proprietary dual combination Target the ~90% of the CF population that carry the F508del mutation 26
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SION-109 (ICL4): Single agent SAD/MAD Phase 1 Summary SION-109 Phase 1 data suggests an encouraging tolerability and PK profile • Dosing generally well tolerated • No SAEs; most AEs were mild to moderate • SAD and MAD PK showed target mean trough concentration from CFHBE assay achieved at 75 mg BID and higher doses • PK consistent with BID dosing Single agent SAD/MAD Phase 1 clinical trial of SION-109 • Evaluated the safety, tolerability and PK profile of single and multiple ascending doses of SION-109 in 102 healthy volunteers; single doses 50 mg to 400 mg, multiple doses 50 mg BID to 150 mg BID • 3:1 randomized, double-blind, placebo-controlled study in the U.S. • SAD/MAD parts dosed as oral suspension; also evaluated the effect of food on PK and bioequivalence of a tablet formulation compared to oral suspension in 15 subjects • FE/BE Part C: 100 mg single dose (x 3) dosing complete 27
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Clinical and Portfolio Strategy
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s Sionna’s development strategy is data-driven with multiple near-term milestones Add-On to SOCDual Combination PreciSION CF Ph 2a POC Trial SION-719 + SOC Ph 1 Healthy Volunteer Dual Combo SION-451 + SION-2222 Ph 1 Healthy Volunteer Dual Combo SION-451 + SION-109 Dual Combination Selection NBD1 Ph 2b Dual Combination Dose Ranging SION-451 + SION-2222 or SION-109 NBD1 TMD1 NBD1 ICL4 NBD1 TMD1 ICL4 Advancement to Ph 2b dose ranging will be data driven and dependent on access to capital 29
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PreciSION CF Phase 2a proof-of-concept trial ongoing: Evaluating low-dose SION-719 added to Trikafta® Phase 2a Endpoints Primary: Safety Secondary: Sweat Chloride, PK Study powered for ≥10 mmol/L SwCl change Study Population Adult CF subjects 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 28 Day Placebo + Trikafta SION-719 + Trikafta 14 Day NBD1 Washout 28 Day Objectives are to demonstrate that NBD1 is mechanistically unique from, and synergistic with the components of Trikafta, and that adding a low dose of NBD1 to Trikafta is associated with improved CFTR function n = ~8 n = ~8 30
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PreciSION CF Phase 2a proof-of-concept trial on-track for readout mid-2026 Definition of Success • Improvement in SwCl of ≥ 10 mmol/L in F508del homozygous patients • Alyftrek Ph 3 data showed a 3.2 mmol/L SwCl improvement in F508del homozygous patients 1 Benchmark Rationale • A 10 mmol/L reduction in SwCl has corresponded to ~3 ppFEV1 improvement • KOLs consistently define this magnitude of change as clinically meaningful • Historically, modulators achieving this level of benefit have shifted treatment paradigm If Successful • Demonstrates NBD1 is mechanistically differentiated • Validates our CFHBE assay predictions • Supports rationale for proprietary NBD1 dual combination therapy A successful POC would demonstrate NBD1 stabilization drives clinically meaningful benefit 1. Keating, Lancet 2025 (Supplement) 31
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Healthy volunteer Phase 1 dual combination trial ongoing: Evaluating safety, tolerability, and PK of SION-451-based dual combos Ph 1 Dual Combo SION-451 + SION-2222 SION-451 + SION-109 14 Day n =12 9 active/ 3 placebo Objective is to evaluate different doses of SION-451 in combination with SION-2222 and with SION-109 in healthy volunteers and select the NBD1-based dual combination to advance to Phase 2b trial in patients with CF n =12 9 active/ 3 placebo Safety/ tolerability and PK will determine next dose(s) SION-451 + SION-2222 SION-451 + SION-109 14 Day Sequential cohorts, doses selected based on data Randomized, double-blind, placebo controlled Combo Doses #2Combo Doses #1 32
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Commercial Opportunity & Unmet Need
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Significant commercial opportunity exists for our NBD1-led franchise to provide a potentially transformative treatment for CF , if approved Growing Target Population More Treatment Options are Needed Large Market Opportunity Primed for Disruption ~106K patients with CF across 94 countries1 ~90% patients have at least one F508del- CFTR mutation2 >2/3 of patients on SOC do not have normal CFTR function4* >6,000 patients have discontinued use of approved CFTR modulators5 >20% of eligible patients are currently not on CFTR modulators6 CNS side effects reported (mood disturbances7,10, depression10, mental fogginess7) Non-responders or patients with tolerability challenges have limited or no alternatives7 ~$12B worldwide revenues of CFTR modulators today8 $15B-$17B opportunity by 20309 1. CFF estimates 2024, 2024 CFF Registry data, 2022 ECFS Registry 2. Taylor-Cousar 2019; 3. Average 2021-2023 prevalence growth in the US and EU4+UK from respective registry data; 4. Konstan, NACFC poster 2022; 5. Vertex 2Q23 Earnings Call Transcript; 6. Vertex 2Q24 Earnings Presentation; 7. Sploletini 2022 JCF; Ibrahim 2023 Front Pharmacol 8. VRTX 3Q25 earnings call; 9. 2025 Wall Street research estimates; 10. Kaftrio EMA SmPC (May 2024) ; * as measured by sweat chloride CF population continues to grow at ~ 2% annually3 34
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Despite advancements in treatment, the unmet need remains high, as many CF patients on treatment do not achieve normal CFTR function 1. Konstan, NACFC poster 2022; 2. Zemanick, JCF 2024; 3. Vertex press release, Feb 5th 2024; * Observational study of 3,131 CF patients from the CFF Registry showing sweat chloride levels pre- and post- treatment of a CFTR modulator Normal sweat chloride <30 mmol/L n = number of participants Bold lines are SC means CHEC-SC Study; All Patients Pre- and Post- Modulator1* Abnormal sweat chloride ≥30 mmol/L Kalydeco (I) Orkambi (LI) Symdeko (TI) Trikafta (ETI) Standard of Care Prescribed CFTR Modulator SwCl (mmol/L) >2/3rd of patients on Trikafta do not have normal CFTR function1,2 as measured by sweat chloride <30mmol/L ~69% of Alyftrek patients in two Phase 3 clinical trials conducted by Vertex did not achieve normal CFTR function3 35
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Data show that lower sweat chloride continues to correlate with FEV₁ gains We believe NBD1 stabilizers are the key to getting more patients to normal CFTR function Reductions in sweat chloride are associated with better long-term outcomes for patients Registry-based study of 25,753 CF patients demonstrated that lower SwCl is a predictor for longer-term survival1 Data from clinical trials shows that FEV1 continues to improves with lower SwCl2 1. McKone, JCF 2015; 2. Zemanick, JCF 2025 36
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Closing
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Sionna’s innovative approach to CFTR restoration has the potential to disrupt the CF market, and is well-funded to execute with cash into 2028 1. VRTX 3Q25 earnings call; 2. 2025 Wall Street research estimates HIGH UNMET NEED IN LARGE MARKET Today’s CF market is ~$12B1, expected to be $15B-$17B by 20302 NOVEL MECHANISM POTENTIALLY TRANSFORMATIVE MEDICINES Proven execution with multiple trials completed and more ongoing Goal is to transform the CF standard of care KEY NEAR-TERM CATALYSTS TLD for Ph 2a POC and Ph 1 HV dual combo trials expected mid-26 Differentiated approach targeting NBD1, a key mechanism to potentially restore F508del CFTR function 38