Transmembrane modulators of CFTR gene leads to improvements in kids with cystic fibrosis

Using small molecule drugs to modulate the cystic fibrosis transmembrane conductance regulator (CFTR) protein improves multiple aspects of cystic fibrosis in paediatric patients, including lung function, CFTR protein function, and nutritional status, according to a recent meta-analysis.

“Beyond the prominent benefits of the therapy, the safety was also favourable compared with that of placebo. The adverse events in the therapy groups were nearly the same as those in the placebo groups,” the researchers said. “Most of the adverse events were mild or moderate; the rate of discontinuation of treatment due to an adverse event in most studies was less than 5 percent.”

A total of 12 studies were included in the quantitative synthesis, of which nine were single-arm studies while three were randomized controlled trials (RCT). Outcomes assessed included lung clearance index_2·5 (LCI_2·5), predicted forced expiratory volume in 1 second (ppFEV₁), sweat chloride levels (SwCl), and scores in the Cystic Fibrosis Questionnaire-Revised (CFQ-R).

Pooled analysis of all included RCTs revealed that active treatment with CFTR modulators led to a significant improvement in ppFEV₁ as compared with placebo (mean difference [MD], 7.91, 95 percent confidence interval [CI], 3.71–12.12). A similar pooled effect was reported for LCI_2·5 (MD, –1.00, 95 percent CI, –1.38 to –0.63). [Front Pediatr 2022;doi:10.3389/fped.2022.937250]

Single-arm studies showed that monotherapy with ivacaftor led to significant improvements in ppFEV₁ (MD, 11.73, 95 percent CI, 9.88–13.59). The same was true when ivacaftor was combined with other agents such as lumacaftor and tezacaftor. Combination regimens likewise led to better LCI_2·5.

RCTs also revealed that CFTR modulators significantly reduced SwCl levels (MD, –35.22 mmol/L, 95 percent CI, –55.51 to –14.92), an effect likewise observed in single-arm studies. In turn, treatment with CFTR modulators significantly improved patients’ quality of life (MD, 4.45, 95 percent CI, 2.31–6.59).

Similarly, active treatment resulted in notable improvements in markers of nutritional status, including weight (MD, 1.53 kg, 95 percent CI, 0.42–2.63), body mass index (BMI; MD, 0.05, 95 percent CI, –0.10 to 0.20), and BMI-for-age z-score (MD, 0.24, 9 percent CI, 0.07–0.54) vs placebo, though none reached statistical significance.

Safety analysis in single-arm studies showed that adverse events were common, with rates ranging from 92.9 percent to 100 percent. The most frequent side effects were coughing, vomiting, nasal congestion, and rhinorrhoea. Rates of serious adverse events were more heterogeneous, ranging from 1.5 percent to 33.3 percent. These were confirmed in RCTs, which recorded similar types of adverse events and found that occurrence rates did not differ among the different CFTR modulators used.

“More well-designed RCTs are needed to support the effectiveness and safety, and extend the indications for younger patients diagnosed with CF, to achieve radical treatment for CF before the development of the disease,” the researchers said.