Compounds Raise Kalydeco’s Efficacy, May Be Future Combo Therapy

Researchers boosted the activity of the cystic fibrosis transmembrane regulator (CFTR), the faulty protein at the heart of cystic fibrosis (CF), by altering the levels of a molecule called cyclic AMP (cAMP).

Their results suggest that cAMP might make an effective add-on therapy to approved CFTR modulators like Kalydeco (ivacaftor).

The study, “Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells,” was published in the journal Nature Scientific Reports.

Although cases of CF involve mutations in the CFTR gene, the amount of variability seen from one individual to the next emphasizes the need for more tailored treatments. Combination treatments — those composed of multiple compounds, each targeting a different factor contributing to CF — represent one way of tailoring treatment.

One such contributing factor is cAMP, a molecule involved in signaling between different cellular components. An enzyme called protein kinase A uses cAMP to tell the CFTR ion channel to open, enabling the movement of chloride ions and water in and out of the cells.

When CFTR malfunctions, as in CF, the normal flow of ions and water is disrupted, and a thick mucus builds in the lungs and other organs.

Researchers at McMaster University, in Canada, knew that they could increase cellular cAMP levels by inhibiting two of its regulators: ABCC4 and PDE-4. Now, they investigated whether doing so would increase CFTR activity and, if so, whether this would enhance the therapeutic effect of Kalydeco, an approved CF therapy marketed by Vertex Pharmaceuticals.

“The interaction of ABCC4 and PDE-4 inhibition to increase cAMP levels to augment CFTR potentiation remains to be explored,” the team wrote.

Using cells derived from human airways, they showed that inhibiting either ABCC4 or PDE-4 alone slightly increased CFTR activity, and that combining them with Kalydeco, a CFTR potentiator, significantly strengthened the effect.

In particular, they observed that Kalydeco given in combination with the ABCC4 inhibitor MK-571 and the PDE-4 inhibitor Roflumilast activated CFTR significantly more than treatment with Kalydeco alone.

Researchers also found that different cAMP inducers — compounds that boost cAMP activity — given along with the combinations also affected the treatments differently. Combinations administered with the cAMP inducer isoproterenol appeared to increase sensitivity to Kalydeco’s action, while forskolin, another inducer, appeared to boost the combination treatments’ effectiveness.

“Further investigation of these combinatorial treatments should be performed,” the researchers noted.

The cells used in this study express a healthy, functional version of CFTR, they also noted, stressing that these results need to be confirmed in cells taken directly from patients with defective CFTR.

“This emphasizes that further investigation of ABCC4 and PDE-4 inhibitors as a potential add-on combinatorial therapy should be performed in primary human airway epithelial cells from a large subset of CF subjects, covering a wide-range of CFTR variants with compromised CFTR expression or function,” the researchers wrote.

Future investigations might also experiment with different CFTR modulators, as some may be more effective than others in combination.

“Our study,” the team concluded, “suggests that cAMP modulation has potential to be pursued as an add-on therapy for the optimal management of CF disease.”