Sionna plans Phase 2a trial of combination therapy for CF

Sionna Therapeutics is planning a proof-of-concept Phase 2a clinical trial to test a combination of two experimental treatments for cystic fibrosis (CF).

The trial, dubbed AscenSION CF, will enroll adults who carry two copies of F508del, the most common CF-causing mutation, and who are taking the approved therapy Trikafta (elexacaftor/tezacaftor/ivacaftor). All participants will switch from Trikafta to the combination of the two treatments, SION-451 and SION-2222, for about a month. The study will evaluate the safety of this switch and its effect on sweat chloride levels.

Announcement of the new study comes shortly after Sionna reported results from another Phase 2a trial, PreciSION CF (NCT07108153). That study had been testing a third experimental therapy from Sionna, SION-719, as an add-on to Trikafta. Although add-on SION-719 was generally well tolerated, data indicated that the additional therapy was no better than a placebo at reducing sweat chloride levels, and Sionna said it would not pursue further development of SION-719 as an add-on to Trikafta.

Sionna has recently completed post hoc analyses — that is, analyses designed and carried out after the study was over and all the data were available — aimed at better understanding why the PreciSION CF trial produced lackluster results. The company said these analyses helped inform plans for the design of the upcoming AscenSION CF trial. Sionna has also announced cost-saving measures including laying off nearly half of its workforce.

“It was important for us to take the time to complete a comprehensive post hoc data analysis to better understand the SION-719 PreciSION CF trial results and their potential implications before determining the right path forward for our dual combination,” Mike Cloonan, president and CEO of Sionna, said in a company press release.

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CF is caused by mutations in the gene that encodes CFTR, a protein that normally helps regulate mucus production. In people with CF, the protein does not function properly, leading to unusually thick, sticky mucus that builds up in organs and drives most CF symptoms. A lack of functional CFTR also leads to elevated levels of sweat chloride (a type of salt molecule), which is why sweat chloride is a useful biomarker for assessing disease activity in CF.

F508del, the most common CF-causing mutation, causes the CFTR protein to be unstable, so it essentially falls apart before it is able to get to the surface of the cell and carry out its functions. The mutation affects a region of the protein called the nucleotide-binding domain 1 (NBD1).

CFTR modulators work to improve the functionality of the CFTR protein in CF patients with specific mutations. Trikafta is a widely approved CF treatment that combines three modulators to help stabilize and improve CFTR function. However, the modulators in Trikafta don’t specifically act on the NBD1. In fact, currently, there are no available modulators targeting this specific region.

SION-451 and SION-719 are both designed to stabilize NBD1. SION-2222, meanwhile, targets other parts of the protein. The combination of SION-451 and SION-2222 showed an acceptable safety and pharmacological profile in early testing done in healthy volunteers.

“Despite the substantial progress made, there remains a significant need for new options for people with CF,” said Gregory S. Sawicki, MD, director of the Cystic Fibrosis Center at Boston Children’s Hospital. “Directly stabilizing NBD1 continues to represent a differentiated approach to addressing the underlying biology of CF. I’m excited to see Sionna proceed with a Phase 2a trial of SION-451 [and] SION-2222, which will be an important next step in further exploring whether the NBD1 biology can translate into meaningful benefit for people with CF.”

Sionna had hoped the PreciSION CF trial would show that the add-on SION-719 increased CFTR activity beyond what was possible with Trikafta alone — but the sweat chloride results suggest this isn’t the case. In the post hoc analysis, researchers found that this may be due to interactions between the experimental therapy and ivacaftor, one of the components of Trikafta, that blunts the effect of NBD1-stabilizing therapy. In addition, pharmacological data showed some patients had lower-than-expected levels of SION-719 or Trikafta in their systems.

“Sionna believes these analyses suggest that SION-719 was biologically active in the trial, but that [pharmacological] outliers and complex interactions between SION-719 and Trikafta may have affected the observed outcome and blunted a potential treatment signal,” the company said.