SION-451 / Sionna Therap - LARVOL DELTA

Investigational New Drug (IND) Application Cleared for SION-451: (The Manila Times) - "The U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application to support the advancement of SION-451 to later-stage development."

IND • Cystic Fibrosis

Data Presented at 2025 North American Cystic Fibrosis Conference: (The Manila Times) - "As previously disclosed, in these Phase 1 trials, both SION-719 and SION-451 were generally well tolerated and exceeded target exposure levels. Based on these data and its cystic fibrosis human bronchial epithelial (CFHBE) model, Sionna believes that its NBD1 stabilizers have the potential to deliver clinically meaningful benefit including up to wild-type levels of CFTR function with SION-719 as an add-on to SOC or with SION-451 in proprietary dual combinations."

P1 data • Cystic Fibrosis

Safety, tolerability, and pharmacokinetics of novel NBD1 stabilizers SION-719 and SION-451 from two phase 1 first-in-human studies (NACFC 2025) - "Based on in vitro CF human bronchial epithelial cell (CFHBE) assay data, the concentration targets for clinically meaningful benefit compared with SOC for both SION-451 and SION-719, as either an add-on to SOC or as part of a dual combination with one of Sionna's complementary modulators (SION-2222 or SION-109), were achieved with single and multiple doses. Novel NBD1 stabilizers SION-719 and SION-451 were generally safe and well tolerated in healthy volunteers in these Ph1 studies. Concentrations were achieved with both compounds that are predicted to deliver additional clinically meaningful benefit based on the CFHBE assay when SION-719 or SION-451 is added to SOC or as part of a novel dual combination with one of Sionna's complementary modulators."

Clinical • First-in-human • P1 data • PK/PD data

Small molecule stabilizers of CFTR NBD1 can increase the protein half-life of the apical glycoform of F508del-CFTR to that of wild-type CFTR (NACFC 2025) - " We utilized metabolic pulse-chase labeling to assess the impact of Sionna NBD1 stabilizers SION-451 and SION-719 on the protein half-life of mature and immature F508del-CFTR glycoforms in the presence and absence of TMD1-directed corrector SION-2222, and ICL4-directed corrector SION-109. Robust increases in CFTR protein half-life were seen in vitro in response to treatment with the novel clinical-stage NBD1 stabilizers SION-451 and SION-719, suggesting that NBD1 instability is a central driver of F508del-CFTR's greatly increased degradation rate. We have previously shown that either SION-451 or SION-719, in dual combination with a complementary modulator, enable full correction of F508del-CFTR and restoration of CFTR function in preclinical CF models. Here we show the effects of NBD1 stabilizers also include the correction of F508del-CFTR's protein half-life defect."

Safety, Tolerability, and Pharmacokinetics of Multiple Dose Combinations of SION-451 and Complementary Modulators SION-2222 and SION-109 in Healthy Participants. (clinicaltrials.gov) - P1 | N=144 | Recruiting | Sponsor: Sionna Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Sionna Therapeutics Announces First Subjects Dosed in Phase 1 Trial Evaluating NBD1 Stabilizer, SION-451, in Proprietary Dual Combinations in Development for the Treatment of Cystic Fibrosis (GlobeNewswire) - "This Phase 1 trial is a randomized, double-blind, placebo-controlled trial in healthy volunteers....Topline data are anticipated in mid-2026, and will inform selection of a dual combination for a planned Phase 2b trial in people living with CF."

P1 data • Trial status • Cystic Fibrosis

Safety, Tolerability, and Pharmacokinetics of Multiple Dose Combinations of SION-451 and Complementary Modulators SION-2222 and SION-109 in Healthy Participants. (clinicaltrials.gov) - P1 | N=144 | Not yet recruiting | Sponsor: Sionna Therapeutics Inc.

New P1 trial • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Stabilizers of CFTR NBD1 synergize with galicaftor (SION-2222) or SION-109 to enable full correction of ΔF508-CFTR (ECFS 2025) - "Sionna is advancing in clinical studies a portfolio of novel NBD1 stabilizers and complementary modulators with a goal to provide pwCF with innovative options. Based on preclinical data, Sionna modulator combinations, if successfully developed and approved, have the potential to provide dramatic improvements in clinical outcomes and quality of life for pwCF."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses and multiple ascending doses of SION-451 in healthy participants (ANZCTR) - P1 | N=96 | Recruiting | Sponsor: Sionna Therapeutics, Inc | Initiation date: Aug 2024

Trial initiation date • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Sionna Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Phase 1 MAD dosing completed for SION-451 and final MAD cohort of SION-719 planned; Interim data in healthy volunteers show potential to provide clinically meaningful benefit to CF patients. Topline data anticipated in first half of 2025; On track to initiate NBD1 Phase 2a proof-of-concept trial in combination with SOC in CF patients and combination MAD trials of an NBD1 stabilizer with a complementary modulator in healthy volunteers in the second half of 2025, with topline data for both anticipated in mid-2026..."

New P2a trial • New trial • P1 data • Cystic Fibrosis

A Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses and multiple ascending doses of SION-451 in healthy participants (ANZCTR) - P1 | N=96 | Recruiting | Sponsor: Sionna Therapeutics, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Sionna Therapeutics Announces Initiation of Two Phase 1 Clinical Trials of SION-719 and SION-451, in Development for Cystic Fibrosis (PRNewswire) - "Sionna Therapeutics...announced that the first subjects have been dosed in two separate Phase 1 clinical trials evaluating the safety, tolerability, and pharmacokinetics of SION-719 and SION-451 in healthy volunteers. SION-719 and SION-451 are product candidates from the company's next generation series of highly potent nucleotide-binding domain 1 (NBD1) stabilizers. The trials are being conducted in Australia under the Clinical Trial Notification (CTN) process."

Trial status • Cystic Fibrosis • Respiratory Diseases

Sionna Therapeutics Announces $182 Million Series C Financing to Advance Clinical Development of Novel Small Molecules in Cystic Fibrosis (PRNewswire) - "Sionna Therapeutics...today announced the closing of a $182 million Series C financing to support the clinical development of first-in-class small molecules designed to fully restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein by stabilizing the first nucleotide-binding domain (NBD1)....This capital raise provides financial flexibility positioning us to execute our clinical development plan with funding through 2026 and multiple value-creating clinical readouts."

Financing • Cystic Fibrosis

Sionna Therapeutics to Present Updates on Clinical Progress in Cystic Fibrosis at 42nd Annual J.P. Morgan Healthcare Conference (PRNewswire) - "Today the company announced it has completed Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) cohorts with SION-638....In the first half of 2024, the Company expects to complete part C of the Phase 1 study, which includes a bioequivalence tablet study and a food effect study....The company also announced plans to advance three additional clinical programs to Phase 1 in 2024, including two compounds from its second series of highly potent NBD1 stabilizers, SION-451 and SION-719, pending results from ongoing Good Laboratory Practice (GLP) toxicology studies. SION-109, which targets NBD1's interface with the ICL4 region, will start Phase 1 in the first quarter of 2024 and will be combined with an NBD1 stabilizer later in development to form a dual modulator combination."

New P1 trial • Trial completion date • Cystic Fibrosis

Sionna Therapeutics Presents Preclinical Data at 2023 North American Cystic Fibrosis Conference Demonstrating Series 2 NBD1 Stabilizers Normalize ΔF508-CFTR Function (PRNewswire) - "Sionna Therapeutics...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."

Preclinical • Cystic Fibrosis

Sionna Therapeutics Presents Preclinical Data at 2023 North American Cystic Fibrosis Conference Demonstrating Series 2 NBD1 Stabilizers Normalize ΔF508-CFTR Function (PRNewswire) - "Sionna Therapeutics...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 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....'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.'"

Pipeline update • Preclinical • Cystic Fibrosis

Sionna Therapeutics Announces Presentation of Preclinical Data on NBD1 Stabilizers at 46th European Cystic Fibrosis Conference (PRNewswire) - "Sionna Therapeutics...today announced the presentation of preclinical data demonstrating the activity of the company's portfolio of compounds targeting the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The results are being presented at the European Cystic Fibrosis Society (ECFS) 46th European Cystic Fibrosis Conference held June 7-10 in Vienna, Austria....Sionna is currently conducting a Phase 1 clinical trial evaluating its lead NBD1 modulator, SION-638, and has nominated two additional NBD1 modulators, SION-719 and SION-451, entering Investigational New Drug application (IND) enabling studies in the second half of 2023....The company is also advancing the development of compounds targeting complementary mechanisms including SION-109, which targets NBD1's interface with the ICL4 region, and SION-676, which targets the TMD1 of CFTR."

Pipeline update • Preclinical • Cystic Fibrosis • Genetic Disorders