Individuals with non-cystic fibrosis bronchiectasis may experience partial cystic fibrosis transmembrane conductance regulator dysfunction (CFTR-RD) that can be identified and treated with highly effective modulator therapy (HEMT), based on data from a cohort study of 41 adults presented at the World Bronchiectasis Conference.

For most individuals with bronchiectasis in the US, the cause of disease is unknown, said lead author B. Shoshana Zha, MD, PhD, an assistant professor and director of the Bronchiectasis and Pulmonary NTM Program (INTEGRATE) at the University of California, San Francisco.

Although bronchiectasis as a result of cystic fibrosis is well described, the clinical impact of partial CFTR-RD among patients with bronchiectasis without cystic fibrosis remains unclear.

In cystic fibrosis, CFTR, a protein that deals with chloride ion transport, doesn’t work well, isn’t produced in sufficient quantities, or is not produced at all, said Nicole Mills, DO, RD, CNSC, associate professor of clinical thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University in Philadelphia.

“Highly effective modulators have been designed to correct the malfunctioning protein, and depending on the type of mutation in CFTR a person has, there are currently modulator therapy options for 90% of people living with cystic fibrosis,” said Mills, who was not involved in the study.

In addition, many people are living with a CFTR-related disorder, meaning that they have one abnormal copy of the CFTR protein, which can manifest as non-cystic fibrosis bronchiectasis. The current study examines the potential of extending HEMT to this population, Mills said. 

“If we identify CFTR dysfunction, there is a direct intervenable treatment that we as clinicians observe can improve symptoms,” said Zha. “This treatment is highly effective modulator therapy (HEMT) that now has broad applicability to many permutations of CFTR dysfunction,” she said.

However, both real-world and regulated clinical trials are needed in order to raise clinician awareness to test for CFTR dysfunction and to determine whether HEMT can improve outcomes in adults whose bronchiectasis is associated with CFTR dysfunction, she said.

Zha and colleagues identified 41 enrolled in the US Bronchiectasis and NTM Research Registry who were clinically diagnosed with CFTR-RD with single-organ disease (bronchiectasis) and were prescribed HEMT. The patients came from seven academic centers, all were non-Hispanic White, 78% were women, and approximately 89% had commercial insurance. The median age was 67 years.

Outcomes were assessed after 6 months of HEMT. The researchers reported data for 36 of the 41 patients, 34 of whom demonstrated improvement in general well-being and significant improvement in cough (P = .001). The researchers further restricted the cohort to 30 individuals who met strict criteria for CFTR-RD, 26 of whom had 6-month follow-up data. Results of the analysis were similar for the smaller cohort, with significant improvement from baseline in cough (P = .009). Bronchitis and pneumonia rates decreased to zero at 6 months from 3-5 at baseline. In addition, adjusted exacerbation rates declined by 90% over the 6 months after HEMT compared to pre-modulator measures based on 19 individuals with complete data (incidence rate ratio, 0.10; 95% CI, 0.04-0.29, P < .001).

The findings were limited by the retrospective design and small sample size, and homogenous study population. Incomplete CFTR variant reporting, especially in non-White populations, may drive underdiagnosis and subsequent undertreatment with HEMT for both cystic fibrosis and CFTR-RD, the researchers noted.

However, the results suggest that CFTR-related bronchiectasis is an emerging endotype that responds well to targeted therapy, the researchers wrote. Additional work is needed to better define which CFTR-RD patients would benefit from HEMT, and to assess long-term benefits and tolerability in these patients, they concluded.

The researchers observed improvements in real time in their own clinics, and they want to disseminate the information to inspire a larger, regulated clinical trial, said Zha. Additional limitations of the current study included the observational nature, lack of control patients (as all participants were treated with HEMT), and a lack of standardization of lung function test or sweat chloride test timing around the intervention. A larger trial would ensure that the findings are scientifically and clinically sound, and not just by association, she said.

In the meantime, the results support the value of testing patients with bronchiectasis for CFTR dysfunction, Zha said. “Even if an intermediate sweat chloride concentration and one mutation is found, HEMT may be a reasonable treatment option to improve symptoms for adult bronchiectasis,” she added.

Takeaways and Next Steps

The study findings were not unexpected, said Mills. Although the patients in the current study had one normal copy of CFTR and therefore no diagnosis of cystic fibrosis, their clinical evidence of CFTR dysfunction suggests that improvement in CFTR function would also show clinical improvements, she noted.

Although the current study was limited by the small sample size and homogenous population, the results support the potential value of several larger clinical trials currently underway that are examining highly effective modulators in non-cystic fibrosis bronchiectasis, Mills said.

Currently, access to highly effective modulators is limited for patients who do not have a diagnosis of cystic fibrosis, said Mills. “Appropriate diagnostic testing to identify which patients may benefit from highly effective modulators, such as sweat chloride testing and identifying specific CFTR variants, can take time,” she said. “Identifying bronchiectasis patients with abnormal copies of the CFTR gene who may be candidates for possible treatment with modulator therapy can start now, so that when these medications are more readily available patients can start on treatment,” she added.

The study used data from the Bronchiectasis and NTM Research Registry, which is supported by corporate donors including Zambon; Merck; GlaxoSmithKline; Baxter; Electromed, Inc; Monoghan Medical Corporation; and Tactile Medical. The study itself received no outside funding, and the researchers had no financial conflicts to disclose. Mills had no financial conflicts to disclose.