Summary of Sionna Therapeutics FY Conference Call Company Overview - **Company**: Sionna Therapeutics (NasdaqGM:SION) - **Industry**: Cystic Fibrosis (CF) Treatment - **Founded**: Late 2019, as a spinout from Sanofi - **Mission**: To revolutionize CF treatment using first-in-class NBD1 stabilizers Key Points and Arguments Unmet Need in Cystic Fibrosis - Despite advancements, a significant unmet need remains in CF treatment, particularly in achieving normal CFTR protein function - Only one-third of patients on standard care reach normal CFTR function, indicating a large opportunity for improvement [4][26] Market Opportunity - The CF market is currently valued at $12 billion and is projected to exceed $15 billion by 2030 [4] - Sionna aims to disrupt this market with novel therapies targeting NBD1, which has been historically considered an undruggable target [5][9] NBD1 Target - NBD1 is crucial for correcting CFTR protein function, and Sionna's approach is to stabilize NBD1, which no approved modulators currently do [5][8] - The company has multiple clinical assets targeting NBD1, with promising preclinical data suggesting potential for significant efficacy improvements [9][10] Pipeline Development - **Lead Compounds**: SION-719 and SION-451, both NBD1 stabilizers, have shown positive Phase 1 data and are advancing to Phase 2A studies [10][12] - SION-719 is in a Phase 2A proof-of-concept study called the Precision CF Study, with expected data by mid-2026 [11][19] - SION-451 is being tested in a dual combination study with complementary mechanisms, also expected to yield data in mid-2026 [20][21] Clinical Strategy - The Precision CF Study aims for a clinically meaningful improvement of at least 10 millimoles in sweat chloride, which correlates with a 3% improvement in FEV1 [22][24] - The study design is efficient, requiring fewer than 20 patients, and each patient acts as their own control [22] Competitive Landscape - Current standard of care, Trikafta, has shown significant improvements but still leaves many patients below normal CFTR function [26] - Sionna's approach aims to provide additional options for the two-thirds of patients not achieving normal function, thus addressing a critical gap in treatment [26] Financial Position - Sionna ended Q3 with $325 million in cash, providing a runway into 2028, which supports ongoing development and upcoming milestones [42] Future Outlook - The company is well-positioned to transform CF treatment with its innovative approach and has a strong team and capital to support its strategy [27][45] - Upcoming data releases in mid-2026 are anticipated to validate the efficacy of NBD1 stabilization and its potential impact on CF treatment [44][45] Additional Important Content - The company emphasizes the importance of patient feedback in determining what constitutes a clinically meaningful improvement in CF treatment [24] - Sionna's strategy includes the potential to co-position both the add-on and dual combination therapies in the market, maximizing commercial opportunities [31][32] - The historical challenges in targeting NBD1 are acknowledged, with Sionna leveraging extensive research and development to overcome these hurdles [39][40]

Summary of Sionna Therapeutics FY Conference Call Company Overview - **Company**: Sionna Therapeutics (NasdaqGM:SION) - **Focus**: Development of treatments for Cystic Fibrosis (CF) targeting the NBD1 protein domain Industry Context - **Market Size**: The CF treatment market is currently valued at approximately $11 billion, predominantly controlled by Vertex Pharmaceuticals [3][39] - **Unmet Need**: About two-thirds of CF patients on standard care do not achieve normal CFTR function, indicating a significant opportunity for new treatments [1][3] Core Scientific Insights - **NBD1 Target**: NBD1 has historically been considered "undruggable" due to challenging chemistry and shallow binding pockets [6][7] - **F508 del Mutation**: This mutation affects approximately 90% of CF patients and causes instability in the NBD1 protein, leading to impaired functionality [7][8] - **Efficacy of NBD1 Stabilizers**: Preclinical data suggests that stabilizing NBD1 can achieve efficacy levels comparable to the current triple combination therapy, Trikafta [8][9] Clinical Development - **Current Studies**: - Phase 2A proof of concept study for NBD1 stabilizer 719 and a dual combination study with stabilizer 451 [4][5] - Both studies are expected to yield results in mid-2026 [5][36] - **Study Design**: The precision study will involve a two-way crossover design to assess the efficacy of 719 added to Trikafta, focusing on sweat chloride levels as a primary endpoint [19][21] Financial Health - **Cash Position**: As of Q3, the company reported $325 million in cash, providing a runway into 2028, which supports ongoing clinical trials and development milestones [39] Strategic Insights - **Dual Combination Strategy**: The company aims to combine NBD1 stabilizers with either an ICL4 corrector or a TMD1 corrector to enhance efficacy beyond current treatments [9][36] - **Selection of Compounds**: The decision to use 719 as an add-on and 451 for dual combination is based on their unique profiles and potency at different doses [16][18] Key Milestones - **Upcoming Data**: Results from both ongoing studies are anticipated in mid-2026, which will be critical for determining future strategies [5][36] Additional Considerations - **Assay Confidence**: The CFHBE assay used for testing has shown high predictive validity for clinical outcomes, enhancing confidence in the results [10][12] - **Market Research**: The threshold for clinically meaningful improvement has been set at a 10 millimole per liter change in sweat chloride, based on historical data and expert consensus [25][33] This summary encapsulates the key points discussed during the conference call, highlighting Sionna Therapeutics' strategic focus, clinical development plans, and financial health within the context of the CF treatment landscape.

Financial Data and Key Metrics Changes - The company raised $219 million from its IPO in February 2025, providing significant financial flexibility and a cash runway extending into 2028 [54][55] - The market for cystic fibrosis treatments is currently valued at $11 billion and is projected to grow to $15 billion in the near term [53] Business Line Data and Key Metrics Changes - The company has concluded Phase I trials for both CYON719 and CYON451R2, reporting positive data indicating both compounds were well tolerated and exceeded pharmacokinetic (PK) targets [8][9] - CYON719 will advance into Phase IIa as an add-on to standard care, while CYON451 will be used in a dual combination study [11][12] Market Data and Key Metrics Changes - The company aims to drive incremental clinical benefits above the standard of care, specifically targeting a 10 millimole improvement in sweat chloride levels compared to Trikafta [27][40] - The company is focused on stabilizing the NBD1 region of the CFTR protein, which is critical for correcting cystic fibrosis [18][22] Company Strategy and Development Direction - The company's mission is to transform the standard of care in cystic fibrosis through differentiated NBD1 stabilizers [5][6] - The strategy includes a dual combination approach with NPD-one as the anchor, aiming to achieve fully normal CFTR function for more patients [7][21] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of NPD-one to deliver clinically meaningful benefits, emphasizing the need for further data to guide future decisions [44][52] - The company is optimistic about the upcoming Phase IIa data and its implications for both the add-on and dual combination strategies [42][45] Other Important Information - The company has prioritized two complementary mechanisms, Cyon2222 and Cyon109, for future studies based on their favorable profiles [46][48] - The company plans to conduct a drug-drug interaction (DDI) study to ensure that the addition of CYON719 does not affect the components of Trikafta [34][36] Q&A Session Summary Question: Can you provide an overview of Ciona's story and strategy? - Ciona was formed as a spinout from Sanofi in late 2019, with a mission to transform cystic fibrosis care through innovative therapies [3][4] Question: What are the key milestones for the company in the next 12-18 months? - Key milestones include the initiation of Phase IIa for CYON719 and a healthy volunteer study for CYON451, both expected to yield data by mid-2026 [14][16] Question: How does the company plan to ensure the efficacy of its treatments? - The company aims for a 10 millimole improvement in sweat chloride levels, which has been shown to correlate with meaningful improvements in FEV1 [27][40] Question: What is the rationale behind the dual combination strategy? - The dual combination strategy is expected to provide a differentiated treatment option that could lead to fully normal CFTR function, addressing the limitations of current therapies [21][52] Question: How does the company view the commercial opportunity in the cystic fibrosis market? - The company believes that its dual combination approach could become the new standard of care, with significant commercial potential given the size of the market [52][53]