Modest Benefits of Kalydeco/Lumacaftor Combination for CF Explained in Two Studies

Doctors and pharmacists are constantly on the lookout for potential drug interactions when giving patients medication. As a result of a number of recent in vitro cell studies, a few cystic fibrosis treatments may soon be added to the list of interactions. Two independent teams found some cystic fibrosis transmembrane conductance regulator (CFTR) potentiators (which boost chloride ion flow through CFTRs) and correctors (which enable proper CFTR folding and transport) negate the theoretical benefits of combination therapy.

“While these and other preclinical experiments represent interesting cell biology that can inform our research efforts, what doctors and patients care about—and what we’re focused on—is the benefit the combination [of potentiators and correctors] has on people with cystic fibrosis,” said Zachry Barber, spokesman for Vertex Pharmaceuticals, in a news article. Vertex produces Kalydeco (ivacaftor) and is developing lumacaftor, both of which are cystic fibrosis drugs.

Publishing in Science Translational Medicine, Dr. Gergely Lukacs’ team from McGill University in Canada explored the effects of VX-770 (ivacaftor, a potentiator) administered long-term with VX-809 (lumacaftor, a corrector) on CFTR function and efficiency. The researchers used both cell lines and primary human respiratory epithelia with the ΔF508-CFTR mutation, which most cystic fibrosis patients carry and that impairs CFTR folding. Results of treatment showed ivacaftor destabilized the corrected form of CFTR produced as a result of lumacaftor, reducing the density and function of CFTR at the cell surface.

Also appearing in Science Translational Medicine, an article from Dr. Martina Gentzsch’s laboratory at the University of North Carolina, Chapel Hill demonstrated a dose-dependent reversal of lumacaftor-related benefits by ivacaftor. Again, the corrected version of CFTR was destabilized by ivacaftor, and this reduced CFTR levels and function.

These studies both contrast and support previous studies in the laboratory and the clinic. First, a team of Vertex scientists showed combining Kalydeco and lumacaftor improved CFTR activity in the short-term in cell cultures. This study was published in 2011 in the journal Proceedings of the National Academy of Sciences. The new studies discussed herein were both long-term, which may explain the discrepancy.

Second, and of great relevance to cystic fibrosis patients seeking better treatment options, a Phase 3 clinical trial for Kalydeco and lumacaftor combination treatment showed only modest improvements compared to Kalydeco-only treatment for the rare mutation form of cystic fibrosis. Yet in the common mutation form, “Kalydeco was a home run. This was a double,” according to Mark Schoenebaum of ISI International. Perhaps the reason for the results, which were not as stellar as would be expected based on preclinical data, is explained by the two new studies.

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Kalydeco is effective in helping “locked CFTR” found in the rare mutation form (G551D) of cystic fibrosis. Yet it is ineffective for helping CFTR protein folding, which is defective in the common mutation form (ΔF508-CFTR) of cystic fibrosis. Although it seems logical that a corrector molecule would enable a proper CFTR to find its way to the cell surface so that a potentiator could help it function, this is not the case for Kalydeco and lumacaftor.

All hope is not lost for this theory. The two new studies suggested alternate combinations for corrector and potentiators. P5, which has yet to be optimized as a drug, is a potentiator that does not share the interference issues of Kalydeco. VX-661 is another option for a corrector. If this or other combinations are desired to be further pursued, Dr. Gentzsch stated that her team’s cell-culture system could be used to screen next-generation potentiators and correctors. These preclinical studies would be valuable to all cystic fibrosis patients, regardless of mutation type.