Experimental CFTR modulators show promise in preclinical tests
Therapies improve function of most common mutated form of protein
Two experimental CFTR modulator therapies being developed by Sionna Therapeutics are able to improve the function of the most common mutated form of CFTR protein that causes cystic fibrosis (CF).
That’s according to new data Sionna presented at the European Cystic Fibrosis Society (ECFS) 48th European Cystic Fibrosis Conference in Milan.
“Preclinical data suggest these compounds, when used in combination, have the potential to dramatically improve clinical outcomes and quality of life for people with CF,” Greg Hurlbut, PhD, co-founder and senior vice president of discovery research at Sionna, said in a company press release.
CF is caused by mutations in the gene that provides instructions to make CFTR, a protein that normally helps control the movement of salt molecules and water in cells. In CF, missing or defective CFTR results in abnormally thick and sticky mucus being produced that builds up in organs to drive most disease symptoms.
CFTR modulators are a class of therapies that are intended to improve the functionality of the CFTR protein in people with specific CF-causing mutations, the most common one being F508del, which causes CFTR to be unstable so that sections of the protein, called domains, don’t fold together properly and it loses function. The F508del mutation specifically affects a domain of the CFTR protein called nucleotide-binding domain 1 (NBD1).
Stabilizing mutated CFTR protein
Sionna’s new therapies, dubbed SION-719 and SION-451, are designed to target NBD1.
“NBD1 instability and defective CFTR domain-domain assembly are the central drivers of CFTR dysfunction that results from the most prevalent CF-causing mutation, F508del … Leveraging over 15 years of research, we’ve had unique success developing novel NBD1 stabilizers that target the NBD1 region of the CFTR protein, a mechanism previously deemed undruggable,” Hurlbut said.
Sionna also is developing complementary CFTR modulators that target other domains of the protein — SION-2222 (galicaftor), which targets transmembrane domain 1 (TMD1), and SION-109, which targets a domain called intracellular loop 4 (ICL4). By simultaneously targeting these domains and NBD1, the modulators should stabilize CFTR protein with the F508del mutation so it can function correctly.
“We are also developing a portfolio of complementary CFTR modulators designed to work synergistically with our NBD1 stabilizers to address domain-domain assembly defects,” Hurlbut said.
In the new preclinical experiments, researchers showed SION-719 and SION-451 can stabilize the NBD1 region carrying the F508del mutation, conferring this mutated region greater stability than is normally seen in the healthy version of the CFTR protein.
In experiments using cells derived from people with CF, using either SION-719 or SION-451 in combination with SION-2222 or SION-109 were shown to correct the maturation of the CFTR protein carrying the F508del mutation to normal levels. Similar results were seen in cystic fibrosis human bronchial epithelial cells also derived from CF patients.
Both SION-719 and SION-451 have been tested individually in healthy volunteers, with results showing each therapy was generally well tolerated on its own. Sionna plans to launch a Phase 2a proof-of-concept trial to test SION-719 as an add-on to standard of care in CF. The company also plans a Phase 1 study to test SION-451 in combination with SION-2222 or SION-109 in healthy volunteers.
The studies are expected to launch later this year, with results anticipated in 2026.
About the Author
