Company: SION
Filing Date: 2025-02-07
Form Type: 424B4
Source: 0001193125-25-022709
Chunk: 160

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-02-07
Form: 424B4
Chunk 160
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 hydration in the airways, digestive system and other organs. When the CFTR protein is not working properly, chloride—a component of salt—gets trapped in cells, as illustrated in
Figure 5. Without chloride to attract water to the cell surface, thick mucus accumulates in vital organs such as the lungs, pancreas and gastrointestinal tract and causes multisystem complications, including respiratory infections, chronic lung
inflammation, poor nutrient absorption and often progressive respiratory failure, which is the primary cause of death in people with CF.

Figure 5. CFTR Regulates Chloride Transport in Epithelial Cells

Source:Favia, 2019

As illustrated in Figure 6, the CFTR protein includes two nucleotide binding domains (NBD1 and NBD2) and two transmembrane domains (TMD1 and TMD2). The
transmembrane domains form the ion channel across an epithelial cell’s membrane. The nucleotide binding domains facilitate the ion channel’s opening and closing by binding and hydrolyzing adenosine triphosphate. There are also four
intracellular loops that link the nucleotide binding domains to the transmembrane domains and are important to regulating ion channel gating.

Figure 6. The CFTR Protein and the F508del Mutation

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The F508del mutation resides in the NBD1 domain near an interface with the fourth intracellular loop,
ICL4, which is particularly critical to the folding of CFTR. When the ICL4 interface is disrupted, as it is by the F508del mutation, CFTR can neither fold nor function properly. The F508del mutation severely destabilizes CFTR’s NBD1 domain,
preventing normal folding and trafficking of CFTR to a cell’s surface and impairing chloride channel function. Support for NBD1 as a key target is based in part on in vitro studies that introduced mutations at other sites on NBD1 that
suppressed the effect of the F508del mutation.

Current Unmet Need and Market Opportunity

While advances in the treatment of patients with CF have improved the lives of patients and resulted in a large commercial market, we believe significant
opportunity remains to provide clinically meaningful benefit to CF patients through the development of NBD1-anchored treatments. NBD1 has long been considered an important target to normalize CFTR function because it is the site where the F508del
mutation—the most common mutation that causes CF—resides. However, attempts by others to stabilize NBD1