Company: SION
Filing Date: 2025-02-03
Form Type: S-1/A
Source: 0001193125-25-018825
Chunk: 176

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-02-03
Form: S-1/A
Chunk 176
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ION-719 (Figure 19, left) and SION-451 (Figure 19, right) increased F508del-NBD1 stability by approximately 16°C. These preclinical models show
the ability of SION-719 and SION-451 to improve the stability of NBD1 as compared to ETI, as measured by light scattering techniques.

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Figure 19. SION-719and SION-451Increased Stability of the NBD1 Domain

SION-719and SION-451Bound to NBD1 with High Affinity

To evaluate the binding ability of our stabilizer candidates, we employed SPR studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain. SPR studies measure changes in the mass of biomolecules immobilized on a metal film. When a small molecule ligand binds to the
immobilized target protein, the refractive index of the metal film changes, resulting in a changed reflection angle of light. In these studies, we found that the strength of the binding interaction was high; the binding affinity of SION-719 to F508del-NBD1 was approximately 4.3 nM and the binding affinity of SION-451 to F508del-NBD1 was approximately 2.4 nM, each expressed as a Kvalue.

SION-719and SION-451Restored F508del Folding and Maturation

In preclinical studies, we evaluated SION-719 and SION-451 in various combinations, including with ETI, galicaftor and SION-109, to assess these combinations’ ability
to improve CFTR folding, maturation and stability and thereby correct F508del-CFTR. Preclinical studies with both SION-719 and
SION-451-based combinations resulted in F508del-CFTR maturation to levels that are similar to wild-type CFTR. We believe these results demonstrated potential synergy
between an NBD1 stabilizer and these complementary modulators.

The results of studies of CFTR maturation in human CF submucosal gland epithelial
(“CFSMEo”) cells by western blot with SION-719 are shown in Figure 20 (top), and the results with SION-451 combinations are shown in Figure 20 (bottom).
Together, the western blots illustrate F508del-CFTR protein in a submucosal-gland epithelial cell line that expresses CFTR, treated with various combinations