Company: SION
Filing Date: 2025-02-07
Form Type: 424B4
Source: 0001193125-25-022709
Chunk: 176

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-02-07
Form: 424B4
Chunk 176
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 a ratio relative to ETI at E max. The vertical bars represent the mean CFTR channel activity (+/- standard error of eight replicates) from a representative study in homozygous F508del CFHBE cells in response to the treatments indicated. The dashed line represents the average response to ETI in each study. Figure 21. SION-719and SION-451 Were Highly Active in the CFHBE Model at E max

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In our CFHBE model, both SION-719 and SION-451, in dual combinations with galicaftor or SION-109, improved in vitroF508del-CFTR activity to wild-type levels, when administered at E max. This was a more than 1.5-fold improvement in CFTR protein activity compared to the improvement in such activity observed with ETI at E maxin the same experiment. As noted above, improvements in CFTR function we observed in our CFHBE model have been highly correlated with mean improvements in sweat chloride levels and mean improvements in lung function. Figure 22. SION-719 and SION-451 Combinations with Galicaftor or SION-109 Were Highly Active in the CFHBE Model at E max

Based on our findings in these preclinical studies and the strong correlation between chloride conductance and improved clinical activity, we believe that both SION-719and SION-451,in combination with a complementary CFTR modulator, have the potential to achieve significant improvement in CFTR function, as measured by sweat chloride levels and lung function, and thereby have the potential to lead to clinically meaningful benefit for CF patients. However, the results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ. We will need to complete additional clinical studies to determine the safety and efficacy of SION-719 and SION-451. Setting Initial Clinical Exposure Targets Based on CFHBE Model To set total plasma concentration targets in our Phase 1 clinical trials with SION-719 and SION-451 in healthy volunteers, we conducted multiple dose response studies of both compounds in our CFHBE model that assessed F508del-CFTR activity as a function of each compound’s concentration in cell culture media supplemented with human serum to 20% by volume. We selected a target exposure for our Phase 1 trials based on an average of these preclinical dose response studies along with studies to define an adequate safety margin. Figure 23 below presents illustrative dose