Trikafta seen to rapidly ease overall inflammation in small study

Triple CFTR modulator's efficacy appears tied to its anti-inflammatory effects

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Trikafta (elexacaftor/tezacaftor/ivacaftor) significantly lowered several pro-inflammatory blood markers with as early as one month of use in cystic fibrosis (CF) patients carrying F508del — the most common CF-causing mutation — and in parallel with gains in lung function.

These are the findings of a small study that suggest that Trikafta’s anti-inflammatory effects also contribute to its long-term clinical benefits.

The study, “Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del,” was published in the journal Plos One.

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Triple CFTR modulator therapy available as Kaftrio in Europe

CF is caused by mutations in both copies of the CFTR gene that lead to the production of a faulty CFTR protein or no protein, ultimately impairing the flow of salt and water in cells. This results in the buildup of a thick mucus in several organs, including the lungs, where it promotes inflammation.

Trikafta, developed and marketed by Vertex Pharmaceuticals, is a highly effective CFTR modulator meant to increase the functioning of the defective CFTR protein. It is approved in the U.S. to treat CF patients, ages 2 and older, with at least one F508del mutation in the CFTR gene or a CFTR mutation that responds to Trikafta in laboratory studies.

In Europe, where Trikafta is sold as Kaftrio, the therapy is cleared in combination with Kalydeco (ivacaftor) for CF patients of the same age range who carry either two F508del mutations, or one F508del and one mutation resulting in a minimally working CFTR protein.

While several studies support Trikafta’s anti-inflammatory effects, fewer reports have assessed its impact on specific immune signaling pathways, such as inflammasomes, in CF patients.

Inflammasomes, a group of proteins of the immune system, are known to play a key role in the activation of inflammatory responses. The activity of one of these inflammasomes, called NLRP3, has been shown to be suppressed differently with distinct CFTR modulators.

To shed light on this, a team of researchers at the University of Leeds, in England, analyzed data from 19 CF patients (median age of 27; 11 women) with one F508del mutation who were followed at the Leeds Regional Adult CF Unit from September 2020 and February 2021. None had been previously treated with a CFTR modulator.

Patients were analyzed before they started treatment with Trikafta (baseline measures), and again after one month and three months of treatment. Blood samples from healthy people were analyzed as controls.

Significant drop in inflammation-promoting neutrophils seen with use

As expected, Trikafta treatment led to a significant improvement in patients’ CFTR protein activity, as indicated by a significant decrease in their sweat chloride levels at three months. This test involves measuring levels of chloride ions in a person’s sweat, which are abnormally high in people with CF.

Within one month on Trikafta, patients also experienced a significant improvement in lung function. Specifically, a median increase of 10.5% after one month of use was seen in the percent predicted forced expiratory volume in one second (ppFEV1), a common lung function measure based on how much air a person can forcibly exhale in one second. Further ppFEV1 gains were observed after three months.

In addition, the number of neutrophils — a type of white blood cell that first responds to an infection or inflammation — were gradually and significantly reduced with treatment.

Trikafta’s use also significantly lowered NLRP3 inflammasome activity at one and three months, as shown by decreased levels of two NLRP3-dependent cytokines, IL-1beta and IL-18.

For most patients, however, average levels of these cytokines “remained higher than that of healthy control (HC) volunteers,” the researchers wrote.

Treated patients also showed significantly lower levels of TNF and IL-6, two pro-inflammatory cytokines not dependent on NLRP3 inflammasome activity, after three months. No significant changes were observed in other NLRP3-independent and pro-inflammatory cytokines.

Similar results were obtained when certain immune cell subsets were grown in the lab and stimulated with known triggers of the NLRP3 inflammasome. Specifically, Trikafta reduced both NLRP3-dependent and NLRP3-independent pro-inflammatory cytokines in patients’ cells, with the former group still showing levels higher than those found in cells from healthy controls.

Overall, Trikafta is not only “highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to considerably improved long-term clinical outcomes,” the researchers wrote.