Company: SION
Filing Date: 2025-02-03
Form Type: S-1/A
Source: 0001193125-25-018825
Chunk: 166

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-02-03
Form: S-1/A
Chunk 166
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 sweat chloride level improvements of 3 to 8 mmol/L. Approximately 69% of Alyftrek patients in two Phase 3 clinical
trials did not achieve normal CFTR function. These results support our beliefs that NBD1 stabilization is required to meaningfully improve upon the current standard of care and that a high unmet need remains for an alternative therapy that can
provide clinically meaningful benefit to CF patients.

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Research Findings Support NBD1 as a Key Target for Stabilizing F508del-CFTR

Multiple studies by third parties have concluded that NBD1 is a key drug target for correcting the F508del mutation, including in vitro studies
that introduced mutations at other sites on NBD1 that suppressed the effect of the F508del mutation. For example, researchers at Utrecht University and University of Texas Southwestern Medical Center identified a second site NBD1 mutation
(“I539T”) that rescued the misfolding and instability of F508del-CFTR. They concluded the “co-translational rescue of F508del NBD1 misfolding in CFTR by I539T advocates this domain as the most
important drug target for cystic fibrosis.”

At University of Texas Southwestern Medical Center, University of Alabama Birmingham, and McGill
University, a second group of researchers identified additional mutations that suppressed the effect of F508del and which, in in vitro studies, stabilized NBD1 and the NBD1-ICL4 interface and fully restored F508del-CFTR maturation and
function to wild-type levels, as shown in the western blot in Figure 9. A western blot is an assay that uses gel electrophoresis to separate a mixture of proteins, which are then transferred to a solid membrane, and then an antibody is used to
detect a specific protein in the sample. The mature apical CFTR band is seen with wild-type CFTR. Partial restoration is observed with NBD1 stabilization and ICL4 interface restoration individually; full restoration of CFTR function occurred in the
presence of both NBD1 and ICL4 suppressor mutations. Without a suppressor mutation, no F508del-CFTR is produced (Ø).

Figure 9. NBD1 Stabilization Synergizes with Improved Domain-Domain Assembly to Fully Correct F508del-CFTR

Source:Thibodeau, 2010

Research Findings Link Further Improvements in CFTR Function to Improved Clinical Outcomes