PharmacologyTier 1Medical Sciences concept

CFTR modulator mechanisms (potentiators vs correctors - ivacaftor, lumacaftor)

Core concept

CFTR is an ATP-gated apical chloride and bicarbonate channel. Mutation class determines which modulator can work

Class	Defect	Example	Modulator
I	No protein (premature stop)	G542X	None - nothing to modulate
II	Misfolding, degraded in ER - fails to traffic	F508del	Corrector (+ potentiator)
III	Reaches membrane, gating defect	G551D	Potentiator
IV	Reduced conductance	R117H	Potentiator
V	Reduced quantity (splicing)	3849+10kbC>T	Corrector +/- potentiator
VI	Unstable at the surface		Corrector/stabiliser

Potentiator (ivacaftor) - binds CFTR already at the membrane and increases the channel open probability
Corrector (lumacaftor, tezacaftor, elexacaftor, vanzacaftor) - acts as a pharmacological chaperone, improving folding and trafficking so the protein escapes ER degradation
F508del has both a trafficking and a gating defect -> needs a corrector and a potentiator; two correctors acting at different binding sites work better than one

Regimen	Composition	Genotype
Ivacaftor	Potentiator alone	Gating (class III), e.g. G551D; class IV
Lumacaftor/ivacaftor	1 corrector + potentiator	F508del homozygous; modest, superseded
Tezacaftor/ivacaftor	1 corrector + potentiator	F508del homozygous/residual function
Elexacaftor/tezacaftor/ivacaftor	2 correctors + potentiator	At least one F508del - ~90% of people with CF
Vanzacaftor/tezacaftor/deutivacaftor	2 correctors + potentiator, once daily	Broad, including rare variants

Elexacaftor/tezacaftor/ivacaftor effect size - ppFEV1 inc ~14%, sweat chloride dec ~40-45 mmol/L, exacerbations dec ~60%, weight and quality of life inc
- Vanzacaftor/tezacaftor/deutivacaftor gives comparable FEV1 with greater sweat chloride reduction and once-daily dosing
Sweat chloride is the pharmacodynamic biomarker (diagnostic threshold >=60 mmol/L; many treated patients fall below 30)
Lumacaftor is a strong CYP3A4 inducer - the major interaction problem of that combination (hormonal contraception, ciclosporin); tezacaftor and elexacaftor are not
All CFTR modulators are CYP3A4 substrates - dose-reduce with azoles and clarithromycin, avoid rifampicin
Adverse effects: transaminitis (monitor LFTs), rash, headache, cataracts in children (annual ophthalmology), and reported mental health effects with elexacaftor
Class I nonsense mutations gain nothing - the unmet need; read-through agents and gene therapy remain investigational

Modulators are disease-modifying but not curative - conventional therapy continues: airway clearance, pancreatic enzyme replacement, fat-soluble vitamins, exacerbation antibiotics
The population has shifted - CF is now an adult disease; adult physicians manage CF-related diabetes, CF liver disease, osteoporosis, fertility, and transplant
Starting a modulator can cause a transient increase in sputum production, and a marked fall in the need for transplant listing
Australian access is PBS-restricted by genotype and age - genotype is required before prescribing
CFTR dysfunction affects sweat, pancreas, biliary tree, vas deferens and airway - so the benefit is multi-organ, not just FEV1

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