Ongoing Trials, Genetic Breakthroughs Pave the Way for Progress in Bronchiectasis

New developments in bronchiectasis presented at the ATS 2023 International Conference represent a growing interest and progress in advancing the science to address the unmet needs of people living with this disease.

Timothy R. Aksamit, MD
Timothy R. Aksamit, MD, FCCP

Timothy R. Aksamit, MD, FCCP, a pulmonary disease and critical care medicine consultant, professor of medicine, and director of the Mayo Mycobacterial and Bronchiectasis Clinic at the Mayo Clinic, pointed to the cutting-edge work being done on three fronts that were highlighted at the conference: clinical trials evaluating novel agents for the treatment of bronchiectasis, research into the role of genetics and disease presentation, and the study of mucociliary milieu.

He noted that multiple large phase three clinical trials in bronchiectasis involve two of the three pillars of the development of the natural history of the disease: infection (targeted by inhaled antibiotics) and inflammation (targeted by anti-inflammatory agents). The third pillar is the aforementioned mucociliary milieu.

The interventional phase three Trial in Non-Cystic Fibrosis Bronchiectasis Patients with Chronic Lung Infections Treated With Colistimethate Sodium (PROMIS II) is studying the effects of inhaled colistimethate sodium in the treatment of non-cystic fibrosis bronchiectasis in patients chronically infected with Pseudomonas aeruginosa. Investigators are evaluating how the use of colistimethate sodium administered twice daily impacts the frequency of pulmonary exacerbations compared to placebo. In PROMIS I, the annual rate of exacerbations was significantly lower in patients receiving the drug, meeting the primary endpoint of that study.

A Study to Assess the Efficacy, Safety, and Tolerability of Brensocatib in Participants With Non-Cystic Fibrosis Bronchiectasis (ASPEN), now in phase three, is investigating the effects of 10 mg and 25 mg doses of brensocatib compared with placebo on the rate of pulmonary exacerbations over 52 weeks. Brensocatib is a small-molecule, oral, reversible inhibitor of dipeptidyl peptidase 1. Topline results of this study of more than 1,700 adult patients in nearly 40 countries are expected in 2024.

“Developments coming out of these phase three trials will hopefully translate into the availability of U.S. Food and Drug Administration- and European Medicines Agency-approved therapeutic interventions specific to bronchiectasis, which to date has not been accomplished,” Dr. Aksamit said. “Whether this involves inhaled antibiotics, anti-inflammatory agents, or other therapies remains to be defined, but the horizon is bright with the potential for FDA- and EMA-approved therapies.”

Mark Metersky, MD
Mark Metersky, MD, FCCP

Mark Metersky, MD, FCCP, professor of medicine, chief of service in the Department of Medicine, chief of the Division of Pulmonary, Critical Care and Sleep Medicine, and the director of the Center for Bronchiectasis Care, University of Connecticut, said the breadth of current research on bronchiectasis is encouraging.

“We’ve come a long way since 10, 15 years ago, when it was truly an orphan disease with very little interest from scientists, clinicians, or pharma in doing research on bronchiectasis,” Dr. Metersky said. “Now we’re seeing research presented from all three of those entities, clinicians, basic scientists or translational researchers, and the pharmaceutical industry.”

Interest, and by extension research, has also gained momentum by involving the contributory factors of genetics to the phenotypic presentation of bronchiectasis, including cystic fibrosis transmembrane conductance regulator-related disease and primary mucociliary dyskinesia. This represents potentially treatable traits and disease-modifying interventions, Dr. Aksamit said. 

“The third transformative development involves research now being directed to look forward with respect to the integration of the three pillars of infection, inflammation, and mucociliary milieu through complex interactions with modulating the natural course of the disease process. This development will potentially translate into improvements in quality of life, fewer exacerbations, fewer hospitalizations, and an overall decrease in disease burden,” he explained.

These advancements represent progress toward personalized medicine for patients with bronchiectasis, as well.

“Personalized care and individualized medicine have come into full force with respect to bronchiectasis and its impact on potential treatable traits,” Dr. Aksamit said. “Specifically, there are increasing abilities to better define specific inflammatory subtypes involved in bronchiectasis, which may direct potential disease-modifying therapies.”

Bronchiectasis remains a heterogeneous disease with need to further characterize the different types of patients with bronchiectasis so more targeted therapies can be implemented, Dr. Metersky noted.

“Some of the research that was presented is attempting to better define the eosinophilic phenotype,” he said. “Other research is trying to better identify other types of inflammation and the correlation of different types of inflammation with what bacteria may be impacting the patient.”

Another component of individualized medicine reflects genetic profile analysis and opportunities for intervention, such as in CFTR-related disease and alpha-1 antitrypsin deficiency, Dr. Aksamit said. Genetic profiling is beginning to be used more widely to examine contributing factors for complications, such as primary ciliary dyskinesia and immunodeficiencies beyond hypogammaglobulinemia. 

New research also utilized data from the United States Bronchiectasis and NTM Research Registry to answer important questions.

“One of the common concerns of our patients is, are they going to be severely impacted if they get COVID-19,” Dr. Metersky said. “Using data from the Bronchiectasis Research Registry, it looks like bronchiectasis patients don’t have more severe outcomes when they get COVID-19 or generally don’t have severe outcomes. They generally do OK when they have COVID. That’s something that’s comforting to patients that we can tell them when they ask.”

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