New CFTR [cystic fibrosis transmembrane conductance regulator] modulator therapies can offer life-altering benefits to some patients with cystic fibrosis, even those with advanced disease.
Triple combination therapy in cystic fibrosis patients with advanced lung disease appears to improve lung function, and may delay the need for lung transplantation, according to a multicenter analysis of patients taking elexacaftor, tezacaftor, and ivacaftor.
The study participants had a percent predicted forced expiratory volume in 1 second (ppFEV1) of 40% or below, or other high-risk factors. Researchers compared them to control patients who were genetically ineligible for triple combination therapy.
Previous studies of such patients on individual drugs or previous combinations showed increases in lung function in patients with advanced disease, though the magnitude of improvement varied across regimens. “With this improvement, it’s unclear how CFTR modulators should affect lung transplant referral timing,” Brent Bermingham, MD, said during a presentation of the study at the virtual North American Cystic Fibrosis Conference.
“The rationale for our study was that despite patients with advanced lung disease being excluded from phase III trials (of elexacaftor, tezacaftor, and ivacaftor), they are receiving a therapy with an unknown clinical efficacy and safety profile,” said Bermingham, a pulmonary and critical care fellow at the Medical University of South Carolina, Charleston.
Lung transplant referral guidelines recommend that physicians initiate discussions about the potential benefit of lung transplant when FEV1 drops below 50% of the predicted value. Patients should be referred for a transplant when the value is below 50% and rapidly declining (>20% decline in the past 12 months), when it drops below 40% with accompanying predictors of shortened survival, or when it drops below 30%. The guidelines were published before approval of triple combination therapy.
The researchers conducted an open-label retrospective analysis of 60 patients started on triple combination therapy between September 2019 and February 2020 at three centers in the Southeast. They compared percent predicted ppFEV1 values prior to initiation of therapy to ppFEV1 values obtained 2-12 weeks after the start of therapy. Patients on therapy were compared with 10 genetically ineligible controls. The two groups were generally similar aside from genetic status, though 100% of the therapy group had pancreatic insufficiency, compared with 90% of controls (P = .013).
The therapeutic group experienced a 7.8% increase in ppFEV1 after starting therapy (P < .001), compared with a 0.5% decrease in controls (P = .65). Before initiation of therapy, 33% of the therapy group met the criteria for initiating a transplant discussion, while 67% had been recommended for transplant. After therapy, 55% met the criteria for discussion, 33% were recommended for transplant, and 12% no longer met the criteria for discussion of transplantation. Fifty percent of controls were in discussion, and this dropped to 40%, while 50% were referred for transplantation, and this increased to 60%. On therapy, transplant referral candidates had an increase of forced vital capacity from 48.9 to 59.16 (P < .001).
Adverse events were rare, with only one discontinuation that occurred following a lung transplant and was not believed to be treatment related.
“Our study had a large number of patients taken from multiple centers, which suggests generalizabilty and real-world experience,” said Bermingham.
The results are encouraging, said Robert J. Giusti, MD, clinical professor of pediatrics at the New York University and director of the Pediatric Cystic Fibrosis Center.
“We’re all remarking how wonderful patients feel these days. It’s really a disease-altering treatment. But for the high-risk group, whose FEV1 is less than 40%, those are the patients we’re more concerned about because we thought maybe they had too much lung disease, and that they wouldn’t benefit from triple combination. But they seem to be improving, so that’s very reassuring,” said Giusti, who was not involved in the study.
The study received funding from the Cystic Fibrosis Foundation and Dartmouth College. Bermingham and Giusti have no relevant financial disclosures.
SOURCE: Bermingham B et al. NACFC 2020, Abstract 645.
This article originally appeared on Chest Physician.