Sionna Therapeutics (SION) 3rd Annual Guggenheim Healthcare Innovation Conference summary

PreciSION CF findings and interpretation

• August PreciSION CF add-on study of SION-719 plus Trikafta was disappointing; post hoc analysis supported continued conviction in NBD1.

• Trikafta exposure averaged 25%-30% lower with SION-719 than on Trikafta alone; the four-drug interaction was complex and differed from expectations.

• A pre-study midazolam DDI study addressed the expected CYP3A4 interaction, but did not predict the complex interaction observed when all four drugs were combined in patients.

• The biological anti-synergy hypothesis centers on NBD1 stabilizers combined with a potentiator; this behavior is not expected in the planned two-drug regimen without a potentiator.

Dual-combination strategy

• Focus shifts to SION-451, an NBD1 stabilizer, plus SION-2222 (galicaftor), a TMD1 corrector; healthy-volunteer PK showed no interaction like the four-drug combination.

• SION-451 and SION-719 share a scaffold and target; SION-719 has slightly higher potency, while SION-451 achieved higher exposures in phase I healthy-volunteer studies.

• SION-2222 is planned once daily and SION-451 twice daily; once-daily SION-2222 exposure was sufficient without twice-daily dosing.

• Preclinical HBE predictions for SION-451 plus SION-2222 indicate at least standard-of-care function, potentially better and within wild-type CFTR range.

AscenSION CF and development path

• Open-label phase II proof-of-concept study is planned to start in Q1 2027 in the U.S.; proposed design is 28 days of dosing after patients stable on Trikafta switch directly to the dual combination.

• Study is expected to enroll homozygous patients; primary activity readout is sweat chloride, with adherence and dosing consistency informed by PreciSION CF learnings.

• After proof of concept, the anticipated path is dual-combination dose ranging, followed by a phase III study; a single-dose pivotal regimen is the current concept, subject to regulator discussions.

• Development plans contemplate including heterozygous F508del patients; superiority remains the target product profile, while equivalence is the minimum product profile.