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

Key Points

• 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.

Phase 2a Study Misses Sweat Chloride Goal

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.

Safety Profile and Potential Confounders

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 company is reviewing them to inform its translational framework.

During the question-and-answer session, McKee said Trikafta levels showed a noticeable decrease during the SION-719 treatment period compared with the placebo period. She said the magnitude could potentially have affected the treatment outcome, though the pattern did not appear to be driven primarily or entirely by CYP3A4 induction.

Cloonan said the company plans a detailed review of patient-level data, including exposure-response relationships, sweat chloride variability and possible effects from combining the drugs with Trikafta. He added that some participants had sweat chloride responses above the 10 mmol/L threshold, but the overall distribution included both responders and non-responders.

SION-451 Combination Study Meets Phase 1 Objectives

Separately, Sionna evaluated SION-451 in combination with either SION-2222 or SION-109 in a Phase 1 healthy-volunteer study. The trial included 120 participants across 10 randomized, double-blind, placebo-controlled 14-day dosing cohorts, with 60 participants in each combination arm.

The company said it identified combinations of both SION-451 plus SION-2222 and SION-451 plus SION-109 that were generally well tolerated and achieved target pharmacokinetic exposures established before the PreciSION CF data became available.

Based on total data and target coverage, Sionna selected SION-451 plus SION-2222 as its preferred dual combination. The preferred regimen was SION-451 dosed twice daily with SION-2222 dosed once daily.

All SION-451 cohorts using once-daily SION-2222 were generally well tolerated, with treatment-emergent adverse events characterized as mild to moderate. There were no serious adverse events or treatment-emergent elevated liver-function events in those cohorts. One participant discontinued dosing because of a moderate rash.

In cohorts where SION-2222 was dosed twice daily, two participants discontinued because of dose-limiting increases in liver function tests and flu-like symptoms. Sionna said both cases were confounded by factors including potential infection, were transient and resolved without sequelae.

Capital Preservation Actions Underway

Sionna reported approximately $268 million in cash at the end of the second quarter. Cloonan said the company is taking actions to preserve capital while it evaluates the data and considers the path forward for SION-451 and SION-2222.

Chief Financial Officer Elena Ridloff said the company expects to provide an updated view of its cash runway after finalizing details around potential next steps for the SION-451 and SION-2222 program.

About Sionna Therapeutics (NASDAQ:SION)

Sionna Therapeutics is a clinical-stage biotechnology company dedicated to developing next-generation RNA therapeutics for oncology and immunology indications. Leveraging proprietary lipid nanoparticle and coacervate delivery technologies, the company aims to overcome key challenges associated with stability, targeting and immune activation that have historically limited the clinical performance of mRNA-based medicines. Its strategic focus spans both solid tumors and hematological malignancies, as well as selected autoimmune disorders, reflecting a broad ambition to harness the power of messenger RNA in diverse therapeutic areas.

At the heart of Sionna’s approach is a platform that combines optimized ionizable lipids with bespoke surface chemistries to enhance payload delivery, intracellular release and endosomal escape.

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