GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - SIONNA THERAPEUTICS INC

Financial Performance:

• Ended Q2 with $268 million in cash, providing an extremely strong balance sheet.
• Successfully resized the company to prioritize clinical investments for the dual-combination program.
• Extended cash runway into the second half of 2029.

Guidance and Future Outlook:

• Plan to launch a Phase 2 Proof-of-Concept (POC) study for the dual-combination (SC-451 and SC-2222) in Q1 of next year, with top-line data timing to be updated after protocol finalization.
• Next steps include a dose-ranging Phase 2 study followed by a Phase 3 pivotal trial.
• Aiming for a superior Target Product Profile (TPP), with minimum goals of non-inferiority to standard of care (Trikafta).
• Future Phase 3 plans contemplate expanding the patient population from homozygous F508del to include heterozygous patients.

Business Segments and Product Lines:

• Pivoted strategy from a four-drug combination (SC-719 + Trikafta) to a two-drug combination (SC-451 + SC-2222) following disappointing Precision CF data.
• SC-451: NBD1 stabilizer (scaffold same as SC-719 but optimized for higher exposure); dosed BID.
• SC-2222: TMD1 corrector (Gallicator analog); dosed QD.
• The dual combination is projected to achieve CFTR function levels comparable to or exceeding wild-type in healthy volunteer assays.
• Ascension CF (POC study) will involve homozygous patients switching from Trikafta to the dual combination for 28 days.

Market and Competitive Landscape:

• Maintains leadership position in the NBD1 mechanism space.
• Views Vertex's announced 4.0 pipeline (specifically the 828 program) as comparable to Eliquis/AlephTrek data (6.5–9% improvement), not fundamentally changing the competitive dynamic.
• Believes the two-drug NBD1 approach offers a unique differentiation potential to drive benefit beyond current Triple Therapy.
• Monitoring Vertex's upcoming 4.0 data closely but sees no immediate threat to the strategic value proposition of their NBD1 platform.

Risks and Challenges:

• Clinical Trial Failure: Acknowledged the "disappointing" and unexpected negative results from the Precision CF study.
• Drug-Drug Interactions (DDI): Identified complex anti-synergy and reduced Trikafta exposure (25–30%) in the four-drug arm due to unanticipated biological and PK interactions in humans.
• Study Design Execution: Must ensure strict adherence to dosing and site management to avoid the pitfalls seen in the Precision study.
• Regulatory Uncertainty: Final Phase 3 study design (placebo vs. non-inferiority) remains TBD pending data from the upcoming POC study.

Management Commentary and Tone:

• Tone remained resilient and conviction-driven; leadership emphasized that the fundamental NBD1 hypothesis remains intact despite the Precision setback.
• CEO Mike Clonin and CMO Charlotte McKee expressed confidence that the complex anti-synergy observed with the four-drug combination will not recur in the two-drug regimen.
• Management highlighted that the dual-combination approach was the original preferred strategy to compete with Vertex's triple therapy.

Analyst Questions and Answers:

• Why did Precision fail? Management attributed it to a complex PK interaction reducing Trikafta exposure (25-30%) and biological anti-synergy when adding an NBD1 stabilizer to a potentiator (Trikafta).
• Why choose 451 over 719? SC-451 achieved higher exposures in Phase 1 healthy volunteers; while potency is slightly lower than SC-719, it is sufficient for the dual-combo without the potentiator component present.
• Study Design Details: Ascension CF will be a small, open-label, US-only study where patients stabilize on Trikafta and switch to the dual combo; primary endpoint is sweat chloride.
• Competition: Analyst noted Vertex's 4.0 update; management responded that current data suggests a similar profile to AlephTrek, reinforcing Siona's belief that their NBD1 platform offers superior potential.
• Financials: Management confirmed strong liquidity with no immediate solvency concerns due to recent cost reductions.

Other Key Points:

• The "anti-synergy" in the Precision study appears linked to the presence of a potentiator (Trikafta); the dual combination excludes the potentiator, mitigating this specific risk.
• Pre-stimulation activity observed with SC-719 in the four-drug context is not expected to hinder the dual-combo efficacy.
• The company is finalizing the Ascension CF protocol with sites and the Cystic Fibrosis Foundation to ensure robust execution.
• Siona remains the primary biotech innovator focused on the NBD1 stabilization mechanism within the cystic fibrosis market.