Elexacaftor Helpful in Cystic Fibrosis Patients Homozygous for F508del

By Reuters Staff

November 28, 2019

NEW YORK (Reuters Health) - Elexacaftor, in combination with tezacaftor and ivacaftor, improved outcomes in patients with cystic fibrosis (CF) homozygous for the F508del mutation, in a phase 3 trial.

F508del is the most prevalent of the more than 2,000 variants in CFTR, the gene implicated in CF. Up to 90% of patients with CF have at least one copy of this mutation, and almost 50% of patients are homozygous for F508del.

Treatment with the combination of a CFTR corrector (such as tezacaftor or lumacaftor) and a CFTR potentiator (such as ivacaftor) has been associated with improvements in health outcomes.

In an earlier phase 2 study, the addition of elexacaftor, a next-generation CFTR corrector, to tezacaftor plus ivacaftor improved CFTR function and clinical outcomes in CF patients homozygous for F508del.

In the current trial, Dr. Harry G. M. Heijerman of University Medical Center Utrecht, in the Netherlands, and colleagues from 44 sites in four countries evaluated the efficacy and safety of elexacaftor plus tezacaftor and ivacaftor versus tezacaftor plus ivacaftor in 107 patients with CF homozygous for F508del.

The primary outcome, change from baseline in percent predicted FEV1 at week 4, was superior with the elexacaftor combination (by 10.0 percentage points over the combination without elexacaftor; P<0.0001), the researchers report in The Lancet, online October 31.

Sweat chloride concentrations improved to a greater extent with the elexacaftor combination, reaching mean values below the diagnostic threshold for CF.

In the elexacaftor group, mean scores on the CF Questionnaire-Revised respiratory domain improved by 16.0 points, exceeding the four-point minimal clinically important difference. The mean score decreased by 1.4 points in the group without elexacaftor.

Elexacaftor treatment also produced a 1.6 kg greater body weight increase and a 0.60 kg/m2 greater increase in BMI compared with combination treatment without elexacaftor.

Both combinations were generally safe and well tolerated, with similar adverse-event rates in the elexacaftor combination (58%) and tezacaftor plus ivacaftor alone (63%) groups.

"Based on the known impact of the benchmark therapy ivacaftor in a small subset of people with cystic fibrosis, the introduction of elexacaftor plus tezacaftor plus ivacaftor is expected to lead to meaningful improvements in the lives of people with cystic fibrosis homozygous for F508del," the researchers conclude. "This degree of CFTR modulation in such a large proportion of people with cystic fibrosis could profoundly affect the face of cystic fibrosis care."

"Despite the short study period, the improvements in clinically meaningful outcomes are encouraging and suggest that triple combination therapy could have the potential to transform health outcomes for many people living with cystic fibrosis," write Dr. Edith T. Zemanick and Dr. Frank J. Accurso of the University of Colorado Anschutz Medical Campus, in Aurora, in a linked editorial. "We must, however, recognize that this still leaves a substantial group of people who do not carry either a F508del or ivacaftor-responsive mutation without an effective modulator option."

"We do not yet understand how improvements in CFTR activity will affect individuals over a lifetime, including those who already have structural lung disease," they note.

"Despite these cautions," the editorial concludes, "the advent of highly effective modulator therapy for people with cystic fibrosis homozygous for F508del offers genuine hope for individuals with cystic fibrosis and their families."

The U.S. Food and Drug Administration (FDA) approved elexacaftor for CF patients with at least one copy of F508del on October 21.

Dr. Heijerman did not respond to a request for comments.

Vertex Pharmaceuticals funded the study, employed nine of the authors and had various relationships with several others.

SOURCE: https://bit.ly/32MJgk7 and https://bit.ly/32PY6q2

Lancet 2019.