In addition to restoring CFTR protein function in cells, the cystic fibrosis (CF) therapies Orkambi (lumacaftor/ivacaftor) and Symdeko (tezacaftor/ivacaftor combo) significantly reduce the excessive inflammation that damages patients’ lungs, a recent study suggests.
Symdeko seems to be more potent than Orkambi at dampening inflammatory responses.
The study, “Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis,” was published in the journal eLife. The work was primarily funded by the U.K. Cystic Fibrosis Trust.
Recurrent lung infections and excessive inflammation are common in CF, which causes additional damage to the lungs. This inflammatory response seems to be triggered by the inflammasome, a multiprotein complex inside immune cells that detects pathogenic (harmful) microorganisms, including those often found in the lungs of CF patients.
After being activated by microbes, the inflammasome triggers the production of major pro-inflammatory molecules, such as interleukin-1 beta (IL-1 beta) and IL-18 — which are present in high levels in CF patients — initiating a cascade of inflammatory responses.
Inhibiting the inflammasome was seen to reduce the amount of pro-inflammatory molecules, decrease lung inflammation, and improve the clearance of bacteria in mice. But whether addressing the defects in the CFTR protein, rather than the secondary effects of its low activity, might also directly lower inflammasome-related inflammation in CF patients remains unknown.
A team led by researchers at the University of Leeds investigated the effects of Vertex Pharmaceuticals‘ Orkambi and Symdeko (known as Symkevi in the European Union), the latest CFTR modulators approved in the U.K. (and elsewhere), on the overactive inflammation seen in CF patients.
Both therapies contain ivacaftor, a CFTR potentiator that helps to stabilize the CFTR protein once it is at the surface of cells. The other components — lumacaftor in Orkambi and tezacaftor in Symdeko — are CFTR correctors, responsible for ensuring the correct folding of the CFTR protein.
Similar effects were recorded when researchers examined these pro-inflammatory molecules in patients’ blood before and after taking
After three months of treatment, both Orkambi and Symdeko were seen to significantly lower blood levels of IL-18 and tumor necrosis factor (TNF). But Symdeko also reduced
Aiming to establish an easier way of determining the anti-inflammatory effects of CF treatments for future trials, the researchers isolated unstimulated peripheral blood mononucleated cells (PBMCs) — rather than monocytes — from patients. Cells were isolated before treatment, after one month on treatment, and again after three months.
Both Orkambi and Symdeko significantly reduced over time cells’ response to bacterial components, lowering the same pro-inflammatory molecules as seen before. The anti-inflammatory molecule IL-10 also increased over time with both treatments, but again, reductions in pro-inflammatory molecules were more consistent with Symdeko’s use.
Notably, Orkambi and Symdeko’s effects on inflammation lasted only 36 hours, but re-exposing cells to the treatments reduced inflammation as effectively.
“This finding has potential implications for patients who struggle with compliance, as missing a single dose will influence inflammatory cytokine levels, and may lead to unwanted side-effects as well as influencing the effectiveness of the therapy,” the researchers wrote.
These data suggested that “systemic inflammation plays a major role in the pathogenesis of CF and, to our knowledge, this pilot study is the first to demonstrate that CFTR modulators have potent innate anti-inflammatory properties,” the researchers concluded.
The team believes that IL-18 and IL-1 beta are reliable biomarkers to monitor the effects of CF therapies on inflammation in future trials. “We believe our approach creates a template for a candidate cytokine protocol for future evaluation in CF trials of dysregulated inflammation in CF,” they wrote.
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