Phase 1 trial of SION-109 oral therapy doses first volunteer

Small molecule designed to bind to NBD1 region to help restore CFTR function

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by Steve Bryson, PhD |

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The first volunteer has been dosed in a Phase 1 clinical trial evaluating SION-109, an experimental oral treatment for cystic fibrosis (CF), as announced by Sionna Therapeutics, the therapy’s developer.

After receiving the green light from the U.S. Food and Drug Administration, the trial has enrolled healthy volunteers to assess SION-109’s safety and pharmacokinetics, or how it moves into, through, and out of the body.

About 90% of CF patients carry at least one copy of the F508del mutation in their CFTR genes. This mutation destabilizes a region of the CFTR protein called nucleotide-binding domain 1 (NBD1), leading to the protein’s rapid degradation. Without a normal CFTR, the flow of water and chloride ions into and out of cells is disrupted, resulting in the accumulation of thick and sticky mucus in the airways, digestive system, and other organs.

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Sionna developing pipeline of small molecules for CF

Sionna is developing a pipeline of small molecules designed to bind to the NBD1 region with the goal of stabilizing CFTR and restoring its function.

In preclinical studies, the company’s lead oral candidate, SION-638, improved the stability and function of the CFTR protein. When combined with the components of Trikafta, an approved CFTR modulator, SION-638’s effect was enhanced even further. It is currently being assessed in a Phase 1 study with healthy volunteers.

SION-109 is designed to complement and improve SION-638’s stabilizing mechanism of action by binding to the interface between NBD1 and another CFTR region called intracellular loop 4 (ICL4). The combined action of the two therapies aims to fully restore CFTR function.

“Our ability to target NBD1 correction is truly novel, and with SION-109 now entering clinical development, we have the opportunity to develop proprietary combination treatments that have the potential to achieve full CFTR correction,” Mike Cloonan, president and CEO of Sionna, said in a press release.

Sionna’s second-generation NBD1 modulators SION-719 and SION-451 were tested in preclinical studies, which showed each enhanced CFTR stability beyond that of SION-638. Both molecules also fully restored CFTR production and function when combined with CFTR modulators. Also being developed is SION‑676, a molecule designed to bind to another CFTR region called transmembrane domain 1.

The safest and most effective CFTR-targeted candidate therapies have the potential to move on to Phase 2a proof-of-concept studies enrolling CF patients, according to the company.

“Advancing our second investigational drug into Phase 1 is an achievement made possible by the tireless work of our research and development teams, who have deep experience in CF and a sharp focus on advancing these programs rapidly to deliver new options for people living with CF and their families,” Cloonan said.