Company: SION
Filing Date: 2025-02-03
Form Type: S-1/A
Source: 0001193125-25-018825
Chunk: 175

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-02-03
Form: S-1/A
Chunk 175
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 chloride levels as the secondary endpoints. We expect to initiate the Phase 2a clinical trial in the second half of 2025.

Combination MAD Clinical Trials—NBD1 stabilizer + galicaftor or SION-109

Following completion of our ongoing Phase 1 clinical trials of SION-719 and
SION-451 and completion of combination toxicology studies, and our selection of a lead NBD1 stabilizer, we intend to begin one or two separate MAD trials of dual combinations, assessing the safety,
tolerability and PK of our lead NBD1 stabilizer in dual combination with galicaftor and/or SION-109 in healthy volunteers. We anticipate initiating these combination MAD trials in the second half of 2025.
Following the completion of such trials, we intend to select one dual combination to advance into Phase 2b dose-ranging trials in CF patients.

Preclinical Studies

We have used
numerous complementary methods to validate and characterize the activity of our compounds. In addition to the CFHBE model, we have utilized differential static light scattering (“DSLS”) experiments to measure the thermal stability of the
NBD1 protein, surface plasmon resonance (“SPR”) studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain, and CFTR western blot
analysis to assess the impact of NBD1 stabilizers on the folding, maturation and stability of F508del-CFTR. Given the results of these preclinical studies, we believe that we have identified highly potent NBD1 stabilizers with robust preclinical
activity.

SION-719and SION-451Increased NBD1 Thermal Stability

In preclinical studies, SION-719 and SION-451 increased the
stability of the NBD1 domain as measured using DSLS experiments. Light scattering provides a measure of the temperature at which a protein unfolds. As the temperature rises, the CFTR protein unfolds and creates aggregates that interfere with the
passage of light. These preclinical studies evaluated the change in temperature that the protein aggregated as the ratio of the compound to CFTR protein increased, which is an indicator of stability. We also evaluated ETI in these preclinical
studies, and we found that they had no effect on NBD1 thermal stability, as measured by light scattering techniques. Restoration of NBD1 thermal stability has been highlighted as being both necessary and sufficient to correct F508del CFTR folding
and assembly. Both S