Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment.

Summary

Across pooled phase 3 datasets and translational assays, sweat chloride robustly tracks CFTR function and aligns with clinical benefit under CFTR modulators. Achieving sweat chloride <60 mmol/L—and ideally <30 mmol/L—was associated with superior outcomes, supporting sweat chloride as a pharmacodynamic target and surrogate endpoint.

Key Findings

• In vivo sweat chloride strongly correlated with CFTR-dependent chloride current in human bronchial epithelial cells.
• Post-modulator sweat chloride values <30 and 30–<60 mmol/L were associated with better lung function, BMI, PROs, fewer pulmonary exacerbations, and favorable longitudinal lung function change versus ≥60 mmol/L.
• Pooled phase 3 analyses support sweat chloride as a surrogate endpoint reflecting restored CFTR function.

Clinical Implications

Use sweat chloride reduction as a pharmacodynamic goal in CFTR modulator therapy, targeting <60 mmol/L and ideally <30 mmol/L to maximize clinical benefit and guide dose optimization and regulatory endpoints.

Limitations

• Secondary, post hoc analyses; causality cannot be inferred.
• Generalizability may vary by genotype and specific modulator regimens; exact sample sizes not reported in the abstract.

Future Directions

Prospective treat-to-target trials using sweat chloride thresholds to guide dose escalation or combination modulator strategies, and validation across genotypes and age groups.