Combining formoterol and methacholine significantly improves mucociliary clearance in animal models of cystic fibrosis, compared to using either drug alone.
RT’s Three Key Takeaways:
- Drug Synergy: Researchers identified that combining formoterol and methacholine significantly improves mucociliary clearance in animal models compared to using either drug alone.
- Broad Application: The therapy could benefit the 10% to 20% of cystic fibrosis patients who do not respond to CFTR modulators, as well as those with COPD or bronchiectasis.
- Safety Profile: A small human study indicated the combination is safe and well-tolerated, avoiding the airway constriction typically associated with cholinergic agonists given alone.
Stanford Medicine researchers found that a combination of two existing medications improves mucus clearance in animal models with cystic fibrosis (CF), according to a study published in the Journal of Clinical Investigation.
The discovery may provide a new way to reduce chronic lung infections in patients with CF. The research team showed that the drug combination—a beta adrenergic agonist, formoterol, and a low-dose cholinergic agonist, methacholine—was safe and well-tolerated in a small group of people, including healthy volunteers and individuals with CF.
“I really hope this discovery can help CF patients,” said Nam Soo Joo, PhD, a senior research scientist at Stanford Medicine, in a news release. “If these drugs improve mucociliary clearance in people as much as they do in our animal models, we expect this to help remove pathogens from the lungs and reduce patients’ airway infections.”
Addressing Unmet Needs in CF Care
The findings could be particularly beneficial for the 10% to 20% of CF patients who do not respond to targeted medications known as cystic fibrosis transmembrane conductance regulator (CFTR) modulators. While CFTR modulators have improved the lives of many patients, some gene mutations remain incompatible with those drugs.
The researchers found the synergy by accident while testing tissues in a dish. Although CF patients typically have an abnormal response to beta adrenergic agonists and cholinergic agonists can cause airway constriction when used alone, the combination performed differently in testing.
In rats with CF, the drug combination increased mucociliary clearance velocity to approximately 80% of the levels seen in healthy rats. Follow-up experiments on tracheal tissue showed the drugs increase fluid secretion, inhibit fluid absorption, and raise the pH of the secreted fluid, which makes mucus less viscous and more mobile.
Potential for Other Respiratory Conditions
The synergistic medications may also assist patients with other conditions characterized by mucus impairment, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis.
“Patients with other respiratory disorders like chronic obstructive pulmonary disease or bronchiectasis also have mucociliary clearance impairment, but compared with CF, it’s mild,” said Joo. “If we use this drug in other airway diseases, it may improve those patients as well, but we still require large-scale clinical trials to know the optimal combination and concentrations of these drugs.”
The drugs are already approved by the US FDA for other uses. The scientists are now planning clinical trials to test the effectiveness of the combination in CF patients.
The study’s senior author was Carlos Milla, MD, a professor of pediatrics at Stanford Medicine and a pulmonologist who treats children at Stanford Medicine Children’s Healthcare. Researchers from the University of Alabama, the University of Saskatchewan, the Friedman Advanced Research Institute at Mount Sinai Medical Center, and the University of Iowa also contributed to the study.
