Sionna Therapeutics (SION) Study update summary

Key findings and post hoc analysis

• Post hoc analysis of the PreciSION CF Phase IIa trial identified three participants with dosing non-adherence, PK outliers, and lower Trikafta exposures as confounding factors, which limited the observed treatment effect; excluding these participants showed a mean placebo-adjusted sweat chloride reduction up to -8.6 mmol/L, indicating NBD1 biological activity and target engagement.

• Lower exposures of Trikafta components and possible biological interactions with the potentiator ivacaftor may have blunted the observed effect of SION-719 when added to Trikafta.

• The trial's complexity and PK variability highlighted the need for improved adherence monitoring and simpler study designs in future trials.

• No significant trends in FEV1 were observed due to the short study duration and lower-than-expected effect size.

• SION-719 will not be advanced as an add-on to standard of care due to these findings.

Clinical trial design and outcomes

• The PreciSION CF Phase IIa trial used a randomized, double-blind, crossover design in 14 adult CF participants homozygous for F508del on stable Trikafta.

• Primary endpoints were safety and tolerability; secondary endpoints included sweat chloride and pharmacokinetics, with the trial powered to detect a ≥10 mmol/L change in sweat chloride.

• Post hoc analysis excluding confounded participants showed evidence of NBD1 stabilization.

Mechanistic insights and rationale

• Nonclinical data suggest that adding NBD1 stabilizers to Trikafta increases pre-stimulation current, potentially leading to CFTR channel dysregulation and limiting further functional improvement.

• NBD1 stabilizers and TMD1 correctors target distinct regions of CFTR, supporting proper folding, trafficking, and function.

• The dual combination of SION-451 plus SION-2222, which does not include a potentiator, shows CFTR channel behavior more similar to wild type in preclinical models and may avoid the blunting effect seen with SION-719 plus Trikafta.

• Nonclinical studies show that the dual combination of SION-451 plus SION-2222 restores CFTR function to wild-type levels in CF human bronchial epithelial cells.

• The dual combination offers a differentiated two-drug approach compared to current triple-combination therapies.