Trial tests new approach with CFTR modulators for cystic fibrosis
First participants dosed in Phase 1 study of drug combination

The first participants have been dosed in a clinical trial that’s testing some of Sionna Therapeutics’ investigational treatments for cystic fibrosis (CF).
The Phase 1 study (NCT07035990) is testing SION-451 with either SION-2222 or SION-109 in healthy volunteers, with the main goal being to evaluate the safety of these combinations. The study is open to adults, ages 18 to 55, and is being run at two sites in Australia. The results, which are expected in mid-2026, will inform plans for testing CF patients.
CF is caused by mutations that lead to the dysfunction or absence of the CFTR protein, which helps regulate mucus production. A dysfunctional CFTR protein leads to thick and sticky mucus that builds up in organs, driving most symptoms.
SION-451, SION-2222, and SION-109 are CFTR modulators , that is, medicines designed to increase the functionality of the CFTR protein in people with CF caused by certain mutations.
Targeting regions of the CFTR protein
The most common CF-causing mutation, F508del, causes a part of the CFTR protein — called nucleotide-binding domain 1 (NBD1) — to become unstable, leading it to lose its function. SION-451 is designed to target and stabilize this region, which isn’t targeted by any approved CFTR modulator. SION-2222 (galicaftor) and SION-109 target and stabilize other regions of the protein.
By simultaneously targeting NBD1 and the other regions, SION-451 in combination with either of the other therapies should stabilize the CFTR protein with the F508del mutation. In preclinical tests, these combinations corrected the maturation and function of the CFTR protein carrying the F508del mutation to normal levels.
“I’ve spent many years as a pulmonary and critical care specialist caring for CF patients in the clinic, and I’ve been in a unique position to experience the evolution of treatment firsthand,” said Charlotte McKee, MD, chief medical officer of Sionna, in a press release. “At Sionna, our research and understanding of the CFTR protein, and the underlying causes of CF have led us to this exciting point, where we are taking the first ever NBD1-anchored dual combinations forward in clinical trials with the goal of revolutionizing the treatment paradigm for CF patients.”
A previous Phase 1 study in healthy volunteers showed that SION-451 was tolerated well on its own. Another modulator targeting the NBD1 region, called SION-719, was also safe in healthy volunteers. Sionna plans a Phase 2a proof-of-concept clinical trial to test SION-719 in patients. It’s expected to start this year.