Where are we with transformational therapies for patients with cystic fibrosis?

•Several types of small molecules aim to correct the basic defect in cystic fibrosis.•Strategies range from repairing mutant mRNA to stabilizing protein at the cell membrane.•Combinations of small molecule correctors will improve rescue of misfolded protein.•Long term follow up is essential to grasp the full impact of small molecule therapies.•Managing access to approved therapies is as important as developing new therapies.

The disease cystic fibrosis (CF) is caused by a disturbance in the synthesis or function of the CFTR anion channel. Several types of small molecules geared to overcome the underlying defect in specific patient groups are in the clinical pipeline. Two drugs have obtained regulatory approval. The potentiator ivacaftor brings major clinical benefit in patients with CFTR protein expression at the cell membrane; the combination ivacaftor plus corrector lumacaftor brings a modest benefit for patients homozygous for the most common mutation F508del. The busy drug pipeline puts pressure on the finite CF patient population. Improving CFTR function in patients has at times yielded unexpected findings. The initial success with ivacaftor has set high expectations, has pushed drug prices sky high and has resulted in inequity in drug access.