Elexacaftor/tezacaftor/ivacaftor (ETI), a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapy, has improved clinical outcomes and extended life expectancy in patients with cystic fibrosis (CF) since its approval. However, its influence on long-term underlying inflammation—which is a significant driver of lung damage and loss of lung function for patients with CF—remains less clearly defined.1
In a recent study published in Respiratory Research, investigators sought to further characterize this effect by examining ETI’s anti-inflammatory and immunomodulatory activity, with a focus on signaling pathways that may trigger an inflammatory response.2
Between October 2019 and June 2021, a total of 49 people with CF (mean age 36 years old) were followed for 24 months while receiving ETI through a compassionate-use program. Participants underwent clinical evaluations, blood assessments, and pulmonary function testing during follow-up visits at three, six, 12, and 24 months following treatment, as well as sweat testing at baseline.2
The findings showed that ETI treatment was associated with improvements in lung function, measured by percent-predicted FEV1, along with reduced use of intravenous antibiotics.
“The complete molecular mechanisms of ETI remain partially unknown,” said researcher Valentino Bezzerri, PhD, an author of the study. “This study clarifies a potential mechanism of action by demonstrating reduced STAT [signal transducers and activators of transcription] factor phosphorylation, which may contribute to the partial anti-inflammatory effects observed with ETI treatment.”
Investigators indeed noted that ETI may exert selective anti-inflammatory effects by targeting two members of the STAT protein family—STAT2 and STAT5—while restoring CFTR function. STAT2 is known to contribute to chronic inflammation in asthma and psoriasis, while STAT5 is associated with allergic inflammation.3–4
The study’s 24-month follow-up and broader analysis of inflammatory markers provide a more comprehensive view of inflammation in CF than previous studies. However, Dr. Bezzerri, of the Fanconi Cancer Foundation in Verona, Italy, said that ETI therapy does not appear to fully resolve underlying inflammation. This point is highlighted by the fact that while ETI therapy downregulated six pro-inflammatory cytokines, many other markers of inflammation remained unchanged with ETI.
“Other anti-inflammatory strategies should be taken into account, even in the era of CFTR modulators,” he said. “Inflammation should be strictly monitored even in the presence of CFTR modulator therapies. We need to better understand the molecular mechanisms of ETI in order to predict possible long-term side effects.”
Dr. Bezzerri also said that the study had some limitations. Most notably, data on STAT inhibition were derived from a small cohort of patients, all of whom carried the F508del mutation. He also said that research has not found a direct link between STAT activation and CF inflammation but rather offers indirect evidence that janus kinases/STAT inhibition can reduce inflammatory features.
References
1. Petrocheilou A, Moudaki A, Kaditis AG. Inflammation and infection in cystic fibrosis: update for the clinician. Children (Basel). 2022;9(12):1898. doi:10.3390/children9121898
2. Lucca F, Pianazzola A, Meneghelli I, et al. Modulation of immune responses by elexacaftor/tezacaftor/ivacaftor therapy in cystic fibrosis: data from a compassionate use program. Respir Res. 2026;27(1):81. doi:10.1186/s12931-026-03494-9
3. Duodu P, Sosa G, Canar J, Chhugani O, Gamero AM. Exposing the two contrasting faces of STAT2 in inflammation. J Interferon Cytokine Res. 2022;42(9):467-481. doi:10.1089/jir.2022.0117
4. Pfitzner E, Kliem S, Baus D, Litterst CM. The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des. 2004;10(23):2839-2850. doi:10.2174/1381612043383638
