Adding the investigational therapy VX-445 to tezacaftor (VX-661) and Kalydeco (ivacaftor) led to a roughly 10 percent improvement in the lung function of cystic fibrosis (CF) patients with F508del mutations in the CFTR gene in a proof-of-concept Phase 2 clinical trial.
The treatment was effective in patients with one or two F508del copies (the most common CF-causing mutation), and has the potential to treat the underlying cause of CF in approximately 90% of patients, researchers say.
Trial findings were published in the study, “VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles,” was published in the New England Journal of Medicine.
Therapies such as tezacaftor and Kalydeco are designed to counteract the consequences of a faulty CFTR (cystic fibrosis transmembrane conductance regulator) protein, the underlying cause of cystic fibrosis.
Tezacaftor is a CTFR corrector, which acts by improving protein transport to where it should work at the cell surface, whereas Kalydeco is a potentiator, which helps keep the CFTR channel open and functioning, allowing chloride ions to move out of cells.
In the study, researchers examined the effects of VX-445, an experimental oral therapy and CTFR corrector, developed by Vertex Pharmaceuticals. The therapy is designed to enhance CFTR function in people with an F508del mutation in the CFTR gene. This type of mutation prevents the CFTR protein from adopting its correct 3D shape, which flags the protein for a quicker destruction inside cells.
Researchers hypothesized that a triple combo of VX-445, tezacaftor, and Kalydeco would enhance their effects over the CFTR protein and lead to superior clinical benefits in CF patients.
To test this hypothesis, researchers conducted a randomized, placebo-controlled, double-blind, dose-ranging Phase 2 trial (NCT03227471) to evaluate the efficacy of the triple combo therapy in CF patients. The trial was sponsored by Vertex and conducted at the Mater Hospital in Brisbane in Australia.
The study was also accompanied by preclinical tests done in human bronchial cells in the laboratory, to evaluate the effects of the triple combo over CFTR processing, transport, and channel function.
In total, the trial enrolled 123 patients with CF carrying either two copies of F508del or one F508del copy and another mutation conferring minimal function to CTFR. Patients were randomly assigned to receive four weeks of the triple combo (with VX-445 at a dose of 50, 100, or 200 mg once daily) or a placebo.
Compared with the controls, the triple combo therapy resulted in a significant improvement in lung function measures, specifically in that it raised the predicted forced expiratory volume in one second (FEV1) by 11.1%-13.8%. This improvement was seen in patients with one or two F508del mutations, and for all doses of VX-445 tested.
“VX-445, in combination with two existing treatments, has demonstrated lung function improvement of around 10 per cent — which is really significant for cystic fibrosis patients,” Lucy Burr, PhD, a researcher at Mater Research Institute, University of Queensland, and one of the authors of the study, said in a university press release.
“Patients in our trial had significant increases in their lung function that they hadn’t been able to achieve previously. In cystic fibrosis, most patients will die from lung disease, so improving or maintaining their lung function is the mainstay of treatment,” Burr added.
Additionally, in both patient groups (with one or two F508del mutations), salt concentrations in sweat (a measure of CFTR function) were lowered, and patients reported a reduction in respiratory symptoms.
These positive effects were “noted at the time of the initial measurement [day 15] after the start of treatment and was maintained throughout the trial [day 29],” the researchers wrote in the study.
“Adding the extra drug [VX-445] seemed be the key to making the dual combination work much better,” Burr said. “The drug improved the protein function, which we measured through sweat chloride in patients. It also significantly improved their lung function and quality of life — and that was only over a four week period.”
The safety profile of the triple combo was considered acceptable by the researchers. Most adverse events were mild or moderate. The most common adverse events associated with the treatment were cough, increased sputum (coughed-up mucus), infective pulmonary exacerbations, coughing up blood, and fever. No dose-limiting side effects or toxic effects were noted.
Interestingly, the clinical benefits seen in patients were consistent with the in vitro preclinical test results, which revealed that the triple therapy significantly improved the function of the F580del-mutated CFTR protein over any dual combination of tezacaftor and Kalydeco.
“When you’re targeting the actual problem, there’s great potential for these medications to change, and lengthen, the lives of patients with the illness,” Burr said.