Kaftrio effective in CF patients with advanced lung disease: Study

Therapy is sold in the US under the name Trikafta

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Kaftrio (elexacaftor, tezacaftor, and ivacaftor) safely and effectively eases structural lung damage and improves lung function and the quality of life for people with cystic fibrosis (CF) who have advanced lung disease.

That’s according to data from a compassionate use program in the Netherlands that let patients with severely impaired lung function access Kaftrio before its approval in Europe. The therapy is sold in the U.S. as Trikafta.

The results were described in “Radiological and long-term clinical response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease,” which was published in Pediatric Pulmonology.

Vertex Pharmaceuticals’ Kaftrio is the most recently approved CFTR modulator, a class of medications that work by improving the function of the CFTR protein, which is faulty in CF due to mutations in the CFTR gene.

CFTR regulates the movement of water and chloride ions into and out of cells, which is essential for mucus production. CFTR mutations result in abnormally thick and sticky mucus accumulating in organs such as the lungs, causing damage and increasing the risk of infections.

In clinical trials, Kaftrio was highly effective for patients with moderately affected lung function and who carried at least one copy of F508del — the most common CF-causing mutation — or a minimal function mutation that results in a protein that works minimally. The therapy was shown to significantly improve patients’ lung function and quality of life.

Kaftrio was approved in Europe in 2020, but has been available outside clinical trials since 2019 under a compassionate use program. The program is meant for CF patients with advanced lung disease, defined as a ppFEV1 below 40%. A lung function measure, ppFEV1 denotes the amount of air forcefully expelled in one second.

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Gains with Kaftrio in advanced lung disease cases

“Therefore, patients treated in this manner were part of a group with advanced lung disease, for whom the effectivity of this treatment was not established thus far,” wrote researchers at the University Medical Center in Utrecht, the Netherlands, who evaluated data from 18 patients (11 men, seven women) who started Kaftrio in a compassionate use setting between September 2019 and September 2020. The patients had a mean age of 34 at the start of treatment and were followed for up to two years.

Of the nine patients with two F508del copies, six had been previously treated with the CFTR modulator Orkambi (lumacaftor and ivacaftor), two were on the CFTR modulator Symdeko (tezacaftor and ivacaftor), and one wasn’t on a CFTR modulator due to previous side effects with Orkambi.

Of the nine patients with one F508del copy and a minimal function mutation, one was being treated with Orkambi under compassionate use.

After three months of treatment, there was a significant decline in sweat chloride levels (a way to assess CFTR function) and in structural lung damage, such as less mucus plugging and a reduction in the wall thickness of airways as seen on chest CT scans.

“Newly provided information through this study is that some of the changes in the lungs seen on CT thorax are reversible upon treatment, even after a short treatment duration,” the researchers wrote.

Patients also saw significant quality of life improvements that weren’t limited to respiration, but also included physical, vitality, health, and role domains.

Kaftrio was also associated with a significant improvement in ppFEV1 and body mass index (a ratio of height to weight), and a significant reduction in lung exacerbations and hospitalizations at all evaluated times up to two years of treatment.

“Gain in ppFEV1 is lower compared to the phase [3] trials that included patients with moderately affected lung function and similar to most published studies in pwCF [people with CF] with severely affected lungs,” the researchers wrote, adding Kaftrio’s effects on sweat chloride and the quality of life respiratory domain were similar to those reported on Phase 3 trials, but a “reduction in exacerbation rate was even more evident in [the] study … possibly due to the higher [starting] exacerbation rate in the group with severe lung damage.”

Lung infections, side effects with Kaftrio

Regarding lung infections in the two years before starting Kaftrio, the sputum of 15 patients (83.3%) was positive for P. aeruginosa, nine (50%) for S. aureus, one (5.6%) for M. abscessus, and 11 (61.1%) for Gram-negative bacteria.

In the first two years of treatment, P. aeruginosa disappeared in one patient, S. aureus in three patients, and Gram-negative bacteria in four. Six showed no changes and five stopped having a cough that produced mucus, so there was no sputum to analyze.

Kaftrio was generally well tolerated, with no side effects related to the treatment and no discontinuations due to side effects.

These findings highlight that “pwCF with advanced lung disease experience relevant clinical benefit after [two] years of treatment with [Kaftrio] in a compassionate use setting,” the researchers wrote. “We expect that the effects seen in our study group will be generalizable to other patients starting [Kaftrio] with comparable disease characteristics, such as poor FEV1 and high exacerbation rate.”