Orkambi’s anti-inflammatory benefits seen in a real-world study

Pro-inflammatory cytokines were reduced in patients after 1 year on Orkambi

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by Steve Bryson, PhD |

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Beyond improving lung function, Orkambi (ivacaftor/lumacaftor) has potent anti-inflammatory benefits that may limit immune-related lung damage in people with cystic fibrosis (CF), according to a real-world study.

Researchers found that one year of treatment significantly reduced the levels of pro-inflammatory signaling molecules in the bloodstream and airways of CF patients. Moreover, measuring these molecules in blood and sputum is a relatively non-invasive way to monitor disease-related inflammatory activity and the impact of therapeutics, they suggest.

The study, “ROCK STUDY in CF: sustained anti-inflammatory effects of lumacaftor–ivacaftor in sputum and peripheral blood samples of adult patients with cystic fibrosis—an observational study,” was published in the journal BMJ Open Respiratory Research.

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Mucus build-up can trigger inflammatory response, resulting in lung damage

CF is caused by inherited defects in the CFTR channel, a protein that regulates the flow of chloride ions and water across cell membranes. Such defects alter the water balance in tissues and lead to the build-up of thick and sticky mucus.

In the lungs, mucus build-up can trigger an inflammatory response, resulting in lung damage. These responses are characterized by elevated levels of pro-inflammatory immune signaling proteins called cytokines in the lungs and bloodstream, likely contributing to tissue damage.

CFTR modulators are a class of widely-approved medicines designed to correct certain defects in CFTR protein. Orkambi is one such therapy that combines lumacaftor, a CFTR corrector that helps with protein production, and ivacaftor, a CFTR potentiator that holds channels open to help restore the flow of ions.

While reports demonstrate that oral Orkambi treatment improves lung function, body weight, and quality of life, “there is limited data on the effect of CFTR modulation on inflammation in patients with CF,” wrote researchers from Cork University Hospital, in Ireland.

To fill this gap, the team collected blood and sputum samples from 44 patients (75% male), 16 years and older, who were treated at the hospital to measure the levels of pro-inflammatory cytokines before and after one year of Orkambi. All participants had the F508del mutation in both CFTR gene copies, as required to be eligible for Orkambi treatment.

Our real-world study shows that in addition to ensuring significant improvements in parameters of lung function,… [Orkambi] therapy produced sustained improvements in both circulatory and airway inflammation.

Intravenous antibiotic use dropped by 68% in first year of treatment

After three and 12 months of therapy, there was an early and sustained improvement in mean lung function, and a significantly reduced sweat chloride concentration, an indicator of improved CFTR function.

The need for intravenous (into-the-vein) antibiotics dropped by 68% in the first year of treatment compared with the year before, as did the mean number of pulmonary exacerbations, and hospitalizations for exacerbations, per patient.

Blood tests showed Orkambi significantly reduced the levels of three pro-inflammatory cytokines — TNF-alpha, interleukin-1-beta (IL-1-beta), as well as interleukin-8 (IL-8), a cytokine well known to attract large numbers of inflammatory immune cells to the lungs in CF patients. No change in pro-inflammatory interleukin-6 (IL-6) or anti-inflammatory interleukin-10 (IL-10) was seen.

A comparison of bloodstream cytokines to clinical features showed patients with elevated IL-1-beta had worse lung function before and after one year of treatment. Likewise, those with high levels of IL-6 had a lower body mass index, a measure of body fat.

Consistent with blood test results, Orkambi treatment significantly reduced sputum levels of TNF-alpha, IL-1-beta, and IL-8, but also of IL-6. No changes in IL-10 levels were detected. Again, high sputum IL-1-beta was linked with impaired lung function before and after one year of therapy.

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High levels of cytokines linked to more intravenous antibiotic use

Last, the team explored relationships between cytokines and pulmonary exacerbations, as indicated by the number of intravenous antibiotic courses administered at home or in the hospital, before and after treatment.

Elevated TNF-alpha, IL-1-beta, and IL-8 in sputum samples significantly correlated with more intravenous antibiotic courses, as did high IL-6 and IL-1-beta in blood samples, “suggesting subjects with high cytokine levels tend to exacerbate more compared with subjects with lower cytokine levels,” the researchers wrote.

No treatment discontinuations were reported, and blood tests for liver health were within the normal range.

“Our real-world study shows that in addition to ensuring significant improvements in parameters of lung function,… [Orkambi] therapy produced sustained improvements in both circulatory and airway inflammation,” the researchers concluded.