Sionna Therapeutics, Inc.

Pipeline Updates

NBD1 Stabilizers

•Initiated PreciSION CF Phase 2a Proof-of-Concept Trial with SION-719: In October 2025, Sionna announced initiation of the PreciSION CF Phase 2a proof-of-concept (POC) trial (NCT07108153) evaluating nucleotide binding domain 1 (NBD1) stabilizer SION-719 as an add-on to the current standard of care (SOC) in CF participants. The trial will evaluate the safety, tolerability, and pharmacokinetics (PK) of SION-719 when administered with SOC and assess change in CFTR function as measured by sweat chloride levels. Topline data from this trial are anticipated in mid-2026. Sionna also completed a successful drug-drug interaction study with midazolam, a sensitive CYP3A4 substrate, which confirmed that SION-719 can be dosed in combination with Trikafta®, the current SOC, according to its label.

•Initiated Phase 1 Dual Combination Trial with SION-451 and Complementary Modulators: In August 2025, Sionna announced initiation of the Phase 1 trial (NCT07035990) evaluating SION-451 in proprietary dual combinations with SION-2222 (galicaftor), a transmembrane domain 1 (TMD1)-directed CFTR corrector, and with SION-109, an intracellular loop 4 (ICL4)-directed CFTR corrector, in healthy volunteers. Topline data from this trial are anticipated in mid-2026.

•Investigational New Drug (IND) Application Cleared for SION-451: The U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application to support the advancement of SION-451 to later-stage development.

•Data Presented at 2025 North American Cystic Fibrosis Conference: In October 2025, Sionna presented data at the 2025 North American Cystic Fibrosis Conference (NACFC) in Seattle, Washington. An oral presentation highlighted data from the two single agent healthy volunteer Phase 1 clinical trials of novel NBD1 stabilizers, SION-719 and SION-451. As previously disclosed, in these Phase 1 trials, both

SION-719 and SION-451 were generally well tolerated and exceeded target exposure levels. Based on these data and its cystic fibrosis human bronchial epithelial (CFHBE) model, Sionna believes that its NBD1 stabilizers have the potential to deliver clinically meaningful benefit including up to wild-type levels of CFTR function with SION-719 as an add-on to SOC or with SION-451 in proprietary dual combinations. A poster with new preclinical data showed the impact of NBD1 stabilizers SION-719 and SION-451 on the half-life of F508del-CFTR protein. In preclinical studies, NBD1 stabilizers SION-719 and SION-451 increased the half-life of mature F508del-CFTR protein up to levels seen in wild-type. This effect was apparent when NBD1 stabilizers were used as single agents or when combined with complementary modulators. These data highlight the further differentiation of the NBD1 mechanism of action, which has the potential to improve both the function of CFTR and CFTR half-life up to wild-type levels.