Sionna Therapeutics (SION) TD Cowen 46th Annual Health Care Conference summary

Strategic vision and scientific rationale

• Aims to revolutionize cystic fibrosis (CF) treatment by targeting NBD1, a region critical to CFTR protein function, addressing high unmet need despite current therapies.

• NBD1 stabilizers are designed to directly address the F508del mutation, the most common CF-causing mutation, by improving protein folding, trafficking, and stability at body temperature.

• Preclinical data show NBD1 stabilizers as monotherapy can achieve nearly equivalent efficacy to current triple-combination standards in vitro.

• The dual combination approach, pairing NBD1 with another modulator, is prioritized to potentially normalize CFTR function.

• NBD1 was historically considered undruggable due to shallow binding pockets, but breakthroughs over 15 years enabled clinical progress.

Clinical development and trial design

• The phase II PreciSION CF study evaluates SION-719 (NBD1 stabilizer) as an add-on to Trikafta in F508del homozygous patients, using sweat chloride as the primary mechanistic endpoint.

• The study is powered for a ≥10 mmol/L sweat chloride reduction, a threshold linked to clinically meaningful FEV1 improvement.

• 16-patient, two-way crossover design reduces variability, with each patient serving as their own control.

• Primary endpoint is safety over a two-week dosing period; secondary endpoints include sweat chloride and exploratory efficacy markers.

• Enrollment targets patients with typical, but not normalized, responses to Trikafta, focusing on the middle of the response distribution.

Data interpretation and future directions

• Linear relationship observed between sweat chloride reduction and FEV1 improvement up to current standards; further improvement beyond current therapies remains to be tested.

• The 10 mmol/L sweat chloride reduction is set as the minimum bar for meaningful clinical benefit and future development decisions.

• Dual combination candidates (SION-451 with galicaftor or SION-109) are being evaluated for safety, PK, and assay activity to select the optimal pairing.

• Co-formulation is a future goal, pending selection of the best dual partner.

• Dose-ranging studies are planned as the next step for both dual and add-on approaches.