Sionna Therapeutics (SION) investor relations material

Key data milestones and study design

• Two major data readouts are expected in summer 2026: phase II-A proof-of-concept for 719 NBD1 stabilizer as an add-on to Trikafta, and phase I healthy volunteer data for dual combinations involving 451 NBD1 stabilizer with galicaftor or SION-109.

• The phase II-A study targets a 10 mmol/L sweat chloride improvement, considered clinically meaningful and expected to translate into a 3% FEV1 improvement.

• The dual combination phase I study will assess safety, tolerability, PK/exposure, and efficacy potential to select the optimal combination for advancement.

• Strategic decisions post-data will include whether to advance the add-on, the dual combination, or both, depending on data and capital availability.

• Patient selection for the phase II-A study focuses on those stable on Trikafta with typical responses, aiming for a dynamic range to test NBD1's added benefit.

Clinical and strategic goals

• Achieving a 10 mmol/L sweat chloride reduction is the efficacy bar, set by community consensus as clinically meaningful and superior to current standards.

• Both add-on and dual combination programs aim for at least a 10 mmol/L improvement, with the expectation of corresponding FEV1 gains.

• Dose-ranging studies will follow positive proof-of-concept, maintaining low doses for safety and efficacy, and expanding to both Trikafta and Alyftrek backgrounds.

• The CFHBE assay is central for predicting clinical efficacy and will be validated if the 10 mmol/L target is met.

• Future studies may broaden eligibility to include patients with sweat chloride already in the normal range, but initial focus is on those above 30 mmol/L where unmet need is greatest.

Translational and regulatory considerations

• Strong correlation between sweat chloride reduction and FEV1 improvement underpins the clinical strategy; 10 mmol/L is the threshold where this correlation strengthens.

• The phase II-A study is powered for sweat chloride, but future pivotal studies will include FEV1 as a registration endpoint.

• The CFHBE assay's predictive value is considered applicable to broader F508del mutation groups, supporting future expansion.

• Safety and efficacy data from the dual combination phase I study will guide which combination advances, with both PK and assay data informing the decision.

• The ultimate goal is to move more patients into the functionally cured range (<30 mmol/L), addressing the largest unmet need in CF.