By mimicking the inflamed CF airways of patients in the lab, researchers also established a new preclinical model to study the efficacy of available and new modulator therapies of CFTR (the defective protein in CF) before advancing to clinical trials.
Findings were published in the study, “The Cystic Fibrosis Airway Milieu Enhances Rescue of F508del in a Pre-Clinical Model,” in the European Respiratory Journal.
Over the past decade, a new group of CF therapies called CFTR modulator therapies have emerged. These treatments work by restoring the function of the transmembrane conductance regulator (CFTR) protein, an ion channel defective in CF patients.
There are now three CFTR modulators approved by the U.S. Food and Drug Administration for the treatment of CF, and they are used depending on the type of CFTR mutation the patient has. They are: Orkambi, Kalydeco (ivacaftor), and Symdeko (tezacaftor/ivacaftor and ivacaftor). All three therapies are marketed by Vertex Pharmaceuticals.
Clinical trials testing Orkambi in CF patients with F508del CFTR mutations, the most common CF mutation, demonstrated only modest improvements in lung function, similar to those of conventional therapies, the researchers said.
Recognizing the need to understand what influences the effectiveness of CFTR modulators like Orkambi, a team of researchers at the University of North Carolina School of Medicine investigated if the efficacy of lumacaftor and ivacaftor changed under inflamed conditions such as those found in the airways of CF patients.
Based on earlier studies, the researchers had reason to believe that inflamed airways would enhance the therapeutic benefits of the Orkambi combo.
To reproduce the inflamed airways of CF patients in the lab, researchers exposed bronchial airway cells from CF patients with F508del mutations to material harvested from the airways of excised human CF lungs. This material contained multiple infectious and inflammatory molecules released from the inflamed lungs.
Researchers found that lumacaftor and ivacaftor were more effective at correcting the defects in CFTR when the CF airway cells were under inflammatory conditions.
“We found that under inflammatory conditions, there was more functional CFTR available for hydrating the CF airways,” Carla Ribeiro, PhD, a professor at the UNC School of Medicine and senior author of the study, said in a press release.
According to Martina Gentzsch, PhD, a professor at UNC and first author of the study, this finding is counterintuitive. “We were surprised that the effectiveness of CFTR modulators might depend on the state of the airway, inflamed or not,” she said.
An array of molecular analyses suggested that the inflammatory milieu in CF airways was not leading to the production of more CFTR protein, but rather helped to stabilize the defective protein and avoid its degradation within cells.
Because increased inflammation occurs early in CF lung disease, even patients with mild disease may experience an increase in treatment effectiveness.
Additionally, because CF patients may be under anti-inflammatory therapy, researchers and doctors “need to consider the interference of anti-inflammatory drugs with CFTR modulators in future studies,” Ribeiro said.
According to the team, future studies should explore the association between the inflammatory status of CF patients’ airways and the efficacy of Orkambi or Symdeko combo therapies.
Also, as more CFTR modulator combinations become available, preclinical evaluation of the efficacy of modulators under conditions that mimic native inflamed CF airway epithelia may be critical for the optimization of CF therapies, the team said.