BOSTON — Sionna Therapeutics, a clinical-stage life sciences company dedicated to developing highly effective and differentiated treatments for cystic fibrosis (CF), today announced the presentation of preclinical data on highly potent Series 2 nucleotide binding domain-1 (NBD1) stabilizers, SION-719 and SION-451. These data show that SION-719 and SION-451 fully restore maturation, trafficking, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein to wild-type levels in combination with complementary modulators. The data are being presented at the 2023 North American Cystic Fibrosis Conference (NACFC) in Phoenix, Arizona.
The most common CFTR mutation in CF is ΔF508, which results in NBD1 destabilization that contributes to defective CFTR folding, trafficking, half-life, and function. Sionna is advancing small molecule NBD1 stabilizers, a novel therapeutic class with the potential to fully correct ΔF508-CFTR. The company is conducting a Phase 1 clinical trial of its lead NBD1 stabilizer, SION-638, and two Series 2 candidates, SION-719 and SION-451, are currently in Investigational New Drug (IND) enabling studies. Sionna is also developing complementary intracellular loop 4 (ICL4) and transmembrane domain 1 (TMD1)-directed modulators to use in combination with NBD1 stabilizers.
“Complete pharmacological correction of ΔF508-CFTR will likely require drugs that fully stabilize NBD1, but currently approved modulators have no direct impact on NBD1 and do not fully normalize CFTR function in most people living with CF,” said Greg Hurlbut, Ph.D., Co-Founder and Senior Vice President, Discovery Research. “After over a decade of research, our science team discovered first-in-class modulators that directly stabilize NBD1. We are excited to showcase our previously undisclosed development candidates from a second series of NBD1 stabilizers with significantly improved activity and potency. Our goal is to deliver new therapies of unprecedented efficacy to people living with CF who have ΔF508 and other responsive mutations.”
The data being presented at NACFC 2023 feature results from rigorously validated functional and biochemical assays. For example, differential static light scattering was used to assess the ability of SION-719 and SION-451 to stabilize NBD1, and both candidates increased ΔF508-NBD1 stability by more than 16°C. In a clinically predictive human bronchial epithelial cell (CFHBE) model, both candidates corrected ΔF508-CFTR maturation and channel function to fully wild-type levels when combined with one or more complementary CFTR modulators.
“There is room for improvement over existing CF therapies because the progression of lung disease continues for many patients, and we have not yet achieved fully normalized CFTR function for the majority of people living with CF,” said Mike Cloonan, President and Chief Executive Officer of Sionna. “Preclinical results have demonstrated the activity of our NBD1 stabilizers alone and in combination with our ICL4- and TMD1-directed correctors, and standard-of-care CFTR modulators. SION-638 is progressing well with Phase 1 data expected soon, and now we have an opportunity to advance SION-719 and SION-451 to clinical stage. This portfolio approach will allow us to advance the best compounds to Phase 2a proof-of-concept trials.”
About Sionna Therapeutics
Sionna Therapeutics is a clinical-stage 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 directly 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.
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