Triple Combinations Like Trikafta Effectively Treat CF: Meta-analysis

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by Steve Bryson PhD |

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Triple combination therapies, a mix of CFTR correctors and potentiators, significantly improve lung function, reduce sweat chloride, and enhance the quality of life for people with cystic fibrosis (CF), a meta-analysis of pooled results from multiple clinical trials shows.

The meta-analysis, “Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials,” was published in Frontiers in Pharmacology.

CFTR is a protein responsible for transporting chloride ions across cell membranes, helping control the movement of water in tissues. In CF, a faulty CFTR leads to poor chloride secretion and the formation of abnormally thick mucus, especially in the lungs and the digestive tract. In the lungs, this mucus interferes with breathing and increases the risk of infections.

Triple combination therapies of CFTR correctors and potentiators have significantly improved lung function in CF patients. Correctors bind to faulty CFTR, which stabilizes the protein and helps it reach the cell membrane, while potentiators hold the CFTR channel open so more chloride can pass through.

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In clinical trials, the approved triple combination therapy containing the two correctors elexacaftor and tezacaftor, and the potentiator ivacaftor — marketed as Trikafta in the U.S. by Vertex Pharmaceuticals — improved lung function in patients with at least one F508del mutation in the CFTR gene. This gene encodes the CFTR protein, and that mutation is the most common CF-causing genetic defect.

Researchers China now conducted a meta-analysis of the efficacy and safety of triple combination therapies by pooling the results of six published randomized controlled clinical trials. All these studies were considered to be of high quality.

“To our knowledge, this study is the first meta-analysis evaluating the efficacy and safety of the triple therapy combination in treating CF,” the team wrote.

One study compared the elexacaftor/tezacaftor/ivacaftor combination (Trikafta) against a triple placebo, while three studies evaluated tezacaftor plus ivacaftor as an active control. One study assessed tezacaftor plus ivacaftor or placebo, with or without elexacaftor, and another with and without the CFTR corrector VX-659, a corrector similar to elexacaftor.

The primary outcome measure included a change in the percent predicted forced expiratory volume (ppFEV1) — the volume of air that can be exhaled in one second.

Also examined were changes in the concentration of chloride in sweat, which is higher in CF patients, and health-related quality of life using the Cystic Fibrosis Questionnaire-Revised (CFQ-R).

Using ppFEV1, sweat chloride, and CFQ-R data pooled from all six trials, patients treated with triple combination therapy were compared to those who received triple placebo or active control (tezacaftor plus ivacaftor). The variability, or heterogeneity, among different study results was also reported.

Heterogeneity notes differences in studies when comparing them, things like a trial’s design, how patients were recruited and randomized, doses given to various groups, statistical analyses used, or trial methodology.

The meta-analysis found that the pooled estimate of ppFEV1 change with the triple combination therapy was significantly higher (better lung function) than those given the triple placebo, with significantly low heterogeneity among the studies.

Compared to those in the active control group treated with tezacaftor plus ivacaftor, the pooled estimate of the change in ppFEV1 with triple combination therapy was significantly higher but with significant variability.

In a subgroup analysis of CF patients who carried two F508del mutations — excluding those who have one F508del mutation plus a second minimal function or so-called gating mutation — the pooled estimate of ppFEV1 with triple combination treatment was still higher than active control, but now with significantly low heterogeneity across the studies.

Sweat chloride levels were significantly lower among triple combination therapy patients relative to the triple placebo and active control patient groups. Still, the study variability in both comparisons was significantly high. Subgroup analysis found similar results, but the heterogeneity was not apparent.

The pooled outcome of CFQ-R scores was markedly higher (better quality of life) with the triple combination against both triple placebo and active control. The heterogeneity was uncertain against triple placebo and significantly high against active control.

In the subgroup analysis, the pooled CFQ-R estimate favored triple combination therapy against tezacaftor plus ivacaftor, with low heterogeneity between studies.

The pooled incidence of adverse events with triple combination therapy was similar to that of the triple placebo group, with insignificant heterogeneity, and similar to the active control group, without evident heterogeneity. Most side effects were considered mild or moderate across all three groups, with no apparent difference leading to trial discontinuation.

The most common — similar across all three groups — were cough, a worsening of lung symptoms due to infections, headache, throat pain, and increased sputum with blood.

“The triple therapy combination had highly significant efficacy and safety in treating CF, as compared with placebo or active control,” the researchers concluded. “More well-designed RCTs [randomized controlled clinical trials] are needed to support the efficacy and safety, and extend the indications for younger patients diagnosed with CF, to achieve radical treatment for CF before the development of the disease.”