Sionna Therapeutics (SION) investor relations material

PreciSION findings and interpretation

• The phase IIa PreciSION study missed its expected sweat chloride improvement of at least 10; post hoc analysis suggested NBD1 target engagement, with a 4-9 improvement after excluding three participants flagged for possible non-adherence.

• TRIKAFTA exposure fell an average 25%-30% across its components when combined with SION-719; the cause and effect on sweat chloride were difficult to quantify.

• A further hypothesis is that ivacaftor, TRIKAFTA’s potentiator, may counteract NBD1 stabilization when more CFTR protein reaches the cell surface; management characterized the four-drug combination as potentially anti-synergistic.

• Management said PreciSION’s result does not refute the NBD1 hypothesis; the dual-corrector combination without a potentiator remains the prioritized strategy and next test.

Next clinical study

• A phase II proof-of-concept study of SION-451, an NBD1 stabilizer, plus SION-2222, a TMD1 corrector, is planned to start in Q1 next year.

• The open-label study will switch homozygous patients from TRIKAFTA to the dual combination for 28 days; sweat chloride is the primary activity endpoint.

• Enrollment is expected to target patients similar to PreciSION participants: not yet normal on sweat chloride, with some prior response and room for potential improvement.

• The study is expected to be small and somewhat larger than PreciSION; protocol and enrollment details are being finalized for release as the study starts in Q1.

• Management said the design will incorporate PreciSION learnings on adherence and sweat chloride variability.

Market opportunity and development path

• Management cited community demand for alternatives to TRIKAFTA and ALYFTREK, including for patients with tolerability challenges or insufficient sweat chloride reduction; it described the market as $13 billion and growing.

• If proof-of-concept results support advancement, the next steps are a phase IIb dose-ranging study and then phase III; phase III design will depend on the efficacy profile.

• Phase III could test non-inferiority or superiority; an ALYFTREK phase III study was cited as an analog for non-inferiority, while sufficiently meaningful benefit could support a superiority design.