Cystic Fibrosis CFTR Modulator Pharmacology
Mutation class taxonomy, corrector and potentiator mechanisms, and approved modulator regimens
CFTR Mutation Classes and Drug Targets
|
Class |
Protein Defect |
Modulator Target |
| Class I | Stop codon / absent protein | No protein produced | No approved modulator |
| Class II | Misfolding / trafficking (F508del) | Protein degraded before cell surface | Correctors: elexacaftor, tezacaftor, lumacaftor |
| Class III | Gating defect (G551D) | Protein at surface but won't open | Potentiator: ivacaftor |
| Class IV–VI | Conductance / reduced quantity / instability | Reduced function or amount | Ivacaftor (some); triple therapy (F508del) |
Approved Modulator Regimens
Potentiator
Ivacaftor (Kalydeco)
- Opens gate of CFTR at cell surface
- Class III gating mutations (G551D +95 others)
- STRIVE trial: +10% FEV1, −55% exacerbations
- No benefit in F508del monotherapy
Corrector + Potentiator
Lumacaftor / Ivacaftor
- F508del homozygous only
- Modest: +2–4% FEV1
- Lumacaftor induces CYP3A4 → reduces ivacaftor levels
- Respiratory AEs at initiation
Triple Combination
Elexacaftor / Tezacaftor / Ivacaftor
- ≥1 F508del allele (age ≥2) — covers ~90% of CF
- +14% FEV1, −63% exacerbations
- Near-normal sweat chloride
- CYP3A4 substrate: avoid strong inducers
Corrector vs Potentiator
Corrector: gets misfolded protein to the cell surface (Class II). Potentiator: opens the gate once protein is there (Class III). F508del needs both — dual defect in folding AND gating.
Non-Modulator Therapies
Modulators do not reverse bronchiectasis or clear colonization. Continue: dornase alfa (cleaves neutrophil DNA), hypertonic saline (rehydrates mucus), airway clearance, inhaled antibiotics for Pseudomonas.