Sionna Halts SION-719 After Phase 2a Miss, Eyes SION-451 Combination Path

Sionna discontinued SION-719 as an add-on to Trikafta after its Phase 2a cystic fibrosis trial missed the sweat chloride endpoint, showing a placebo-adjusted change of just −1 mmol/L versus the 10 mmol/L target.

SION-719 was generally well tolerated, but the company is reviewing variability in sweat chloride readings and Trikafta exposure that may have influenced the results.

A Phase 1 study supported the safety and pharmacokinetic profiles of SION-451 combinations; Sionna selected SION-451 plus SION-2222 as its preferred regimen and is preserving capital while determining next steps.

Sionna Therapeutics NASDAQ: SION said its PreciSION CF Phase 2a proof-of-concept study of SION-719 added to Trikafta did not meet its key activity endpoint, prompting the company to discontinue development of SION-719 as an add-on to standard of care for cystic fibrosis. The company also reported that a separate Phase 1 study of proprietary dual combinations based on SION-451 met its safety, tolerability and pharmacokinetic objectives. Sionna is now analyzing the Phase 2a findings and its translational framework to determine potential next steps for the preferred SION-451 plus SION-2222 combination.

The PreciSION CF trial evaluated SION-719 at 30 milligrams twice daily when added to Trikafta in adults with cystic fibrosis who were homozygous for the F508del mutation. The randomized, double-blind, placebo-controlled crossover trial enrolled 15 participants who had been stable on physician-prescribed Trikafta for at least three months before screening. After a 14-day Trikafta run-in, participants received 14 days of SION-719 plus Trikafta and 14 days of placebo plus Trikafta in randomized order, separated by a 28-day washout period. The primary endpoint was safety and tolerability, while secondary endpoints included pharmacokinetics and changes in sweat chloride, a biomarker of CFTR function. Sionna had powered the study to detect a sweat chloride improvement of at least 10 mmol/L, which management said it considered potentially clinically meaningful. Instead, SION-719 produced a mean placebo-adjusted sweat chloride change of negative 1 mmol/L, with a p-value of 0.7.

“We are deeply disappointed to announce that PreciSION CF Phase 2a trial did not meet its key activity endpoint,” President and Chief Executive Officer Mike Cloonan said. “Given these data, we are not continuing development of seven one nine as an add-on to standard of care.” Chief Medical Officer Charlotte McKee said the result was below the company’s threshold for clinically meaningful benefit, was not statistically significant and did not show the expected additional improvement in CFTR function.

SION-719 was generally well tolerated during the 14-day treatment period when added to Trikafta, according to the company. Most treatment-emergent adverse events were mild to moderate, and there were no serious adverse events or overall clinically meaningful trends in adverse events, including liver-function events. The company reported one Grade 3 liver function test increase that occurred at the start of the SION-719 treatment period before dosing and resolved before the end of treatment. One participant discontinued treatment for a reason unrelated to an adverse event. McKee said Sionna observed higher-than-expected variability in individual sweat chloride measurements and differences in Trikafta exposure between SION-719 and placebo treatment periods at the individual participant level. She said those factors do not appear likely to change the trial’s outcome, but the compa...