Company: SION
Filing Date: 2025-03-20
Form Type: 10-K
Source: 0002036042-25-000005
Chunk: 24

Company: Sionna Therapeutics, Inc.
Filing Date: 2025-03-20
Form: 10-K
Item: Item 1
Chunk 24
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 Emax

Based on our findings in these preclinical studies and the strong correlation between chloride conductance and improved clinical activity, we believe that both SION-719 and 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 

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margin. Figure 23 below presents illustrative dose responses of SION-719, as a single agent and in combination with ETI, SION-109 or galicaftor (SION-2222), as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors. The black dotted horizontal line indicates ETI’s improvement in F508del-CFTR activity at Emax, the teal horizontal line indicates our minimum target for clinically meaningful improvement in F508del-CFTR activity based on our CFHBE assay, and the green horizontal line represents the lower bound of the CFTR activity range observed across a panel of eight CFTR wild-type CFHBE donors. The X-axis shows increasing drug concentrations on a logarithmic scale. A roughly two-fold increase over ETI, as seen with SION-719 treatment at its Emax in each of the three combinations, is in the range of wild-type channel activity.

Figure 23. Representative ΔF508/ΔF508 CFHBE Dose-Response of SION-719 as Single Agent and in Combination with ETI, SION-109 or SION-2222

(ETI = 3 μM