Sionna Therapeutics Presents Preclinical Data Demonstrating Restoration of ΔF508-CFTR by Stabilizing NBD1 with SION-638 in Cystic Fibrosis

- Clinically predictive CFHBE model suggests SION-638 restores ΔF508-CFTR maturation, trafficking, and
function to wild-type levels when combined with mechanistically complementary agents -

- Data presented at the North American Cystic Fibrosis Conference –

BOSTON, Mass., Nov. 3, 2022 /PRNewswire/ -- Sionna Therapeutics, a life sciences company dedicated to developing highly effective and differentiated treatments for cystic fibrosis (CF), today announced the presentation of preclinical data that demonstrate the restoration of wild-type function of the cystic fibrosis transmembrane conductance regulator (CFTR) impaired by ΔF508 by stabilizing CFTR's first nucleotide binding domain (NBD1) with SION-638, the company's first-in-class small molecule NBD1 corrector, combined with mechanistically complementary agents. The data are being presented at the Cystic Fibrosis Foundation's North American Cystic Fibrosis Conference (NACFC) 2022 being held November 3-5 at the Pennsylvania Convention Center in Philadelphia.

"We know that full CFTR correction may require NBD1 stabilization, but for decades researchers have concluded that NBD1, as a target, is undruggable," said Greg Hurlbut, Ph.D., Co-Founder and Senior Vice President, Discovery Research of Sionna. "Now we have shown that our novel small molecules successfully bind to this important target in CF, potentially enabling full restoration of CFTR function in people with the ΔF508 mutation. We are encouraged by the data showing that NBD1 stabilization with SION-638 in combination with other complementary modulators led to wild-type correction of CFTR in the predictive CFHBE model."

There are over 100,000 people living with CF around the world. It is a serious, potentially fatal genetic disease caused by a mutation in the CFTR gene that leads to a buildup of mucus in the lungs and airways, impaired pancreatic function and other organ dysfunction. It is estimated that approximately 90 percent of people living with CF have the genetic mutation ΔF508 that causes NBD1 destabilization and leads to impaired folding, trafficking, half-life, and function of CFTR.

Sionna researchers used functional and biochemical assays to evaluate the activity of Sionna's first NBD1 targeted program, SION-638, alone and in combination with Sionna's fourth intracellular loop (ICL4)- and first transmembrane domain (TMD1)-directed correctors, and standard-of-care CFTR modulators. Key findings include:

• SION-638 binds to the NBD1 of CFTR.

           Surface Plasmon Resonance (SPR) was used to evaluate SION-638 binding to human wild-type NBD1
           and two ΔF508-NBD1 isoforms. SION-638 demonstrated 1:1 binding across all three NBD1 isoforms
           with K_D values ranging from 29nM - 48nM.

• SION-638 stabilizes the NBD1 of CFTR.

           Differential Static Light Scattering (DSLS) was used to assess the ability of SION-638 to stabilize
           NBD1. SION-638 increased ΔF508-NBD1 stability by up to 10.4°C. Standard-of-care CFTR modulators
           had no meaningful impact on NBD1 stability.

• SION-638 improves ΔF508-CFTR maturation and trafficking.

           A ΔF508-CFTR-horseradish peroxidase (HRP) trafficking assay was used to quantitate cell surface
          CFTR levels. SION-638 increased cell surface ΔF508-CFTR to wild-type levels when combined with
          complementary modulators.

• SION-638 increases ΔF508-CFTR function.

          CFTR-dependent chloride transport was measured in ΔF508 homozygous human bronchial epithelial
          cells (CFHBE) treated with SION-638 plus standard-of-care CFTR modulators. CFTR channel activity
          achieved wild-type levels when SION-638 was added.

"Currently available modulators increase the function of CFTR, providing eligible patients with clinical benefits, but do not enable most people with CF to achieve normal levels of CFTR function," said Mike Cloonan, President and Chief Executive Officer of Sionna Therapeutics. "We believe NBD1 is essential to normalize the function of CFTR and the production of healthy, freely flowing mucus in the airways, digestive system, and other organs. These data suggest that our NBD1 stabilizers enable multiple potential paths to full restoration of CFTR function for most people with CF, which is unprecedented. We are moving forward aggressively with our development programs and look forward to submitting an Investigational New Drug (IND) application for our first NBD1 corrector, SION-638, and initiating a Phase 1 study in the first half of 2023."

About Sionna Therapeutics
Sionna Therapeutics is a life sciences company dedicated to developing highly effective and differentiated treatments for cystic fibrosis (CF) by normalizing the function of CFTR, the key protein associated with disease progression in CF. Building on over a decade of extensive research on the genetic mutations associated with CF and founded in 2019, Sionna is advancing a pipeline of small molecules engineered to correct the protein defects caused by ΔF508, the most common mutation that affects the CFTR protein. The company has a first-in-class portfolio of programs targeting correction of NBD1, the key and unique mechanism to enable full restoration of ΔF508-CFTR function, and complementary programs targeting ICL4 and TMD1. Sionna's pipeline has the potential to deliver best-in-class efficacy and reach previously unachievable levels of long-term benefit for people with CF. For information about Sionna visit https://www.sionnatx.com/.

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