In my first “Rethinking Drug Action” post, I described how researchers are seeking activators of PARK9, a protein that is mutated in Parkinson’s Disease. In a similar manner, Ivacaftor, a new drug for Cystic Fibrosis (CF), shifts the paradigm from treating CF symptoms to therapeutic treatment of the underlying cause of the disease: defects in the activity of the CFTR ion channel owing to genetic loss-of-function mutation.

In this case the mutation is the rare G551D variant (4-5% of all CF patients) that makes CFTR non-responsive to ATP-dependent channel opening. The more common delta-F508 CFTR mutation is thought to prevent membrane expression of CFTR through misfolding, and indeed, clinical trials showed that ivacaftor alone had no effect on patients with this mutation.

However, for patients with the G551D mutant, where CFTR does reach the membrane but is less active than WT, the drug is very efficacious. In a clinical trial, patients who received ivacaftor were 55% less likely to experience pulmonary exacerbation (defined as a worsening of lung function owing to infection or inflammation) after 48 weeks on the drug. Other markers of CF were also improved during this period.

The exact mechanism of action of ivacaftor is not known. Interestingly, however, ivacaftor enhances spontaneous ATP-independent activity of both G551D-CFTR and WT-CFTR to a similar magnitude. In a recent PNAS paper, researchers propose that ivacaftor affects both WT and G551D in the same way, namely by shifting the equilibrium from the closed (C2) state towards the open2 (O2) state, in essence, “wedging” CFTR open.

In the same paper, the researchers propose that the CFTR transmembrane domains (TMD) may be the site of binding for the drug. In support of this, they note that the drug is relatively hydrophobic and is measured to increase gate opening times regardless of whether it is applied from the cytoplasmic or extracellular side, suggestion membrane permeation and binding to the TMDs.

More studies are needed to prove this mechanism, but it will be very interesting to see how this paradigm-shifting new drug works on the molecular level. In addition, other compounds are in development that aim to enhance the folding and membrane expression of the more common DF508 mutation. Perhaps combination therapy with new compounds for DF508 and ivacaftor together will aid those CF patients who currently are not helped by ivacaftor alone.