In the Journals

Outcomes better with triple therapy in cystic fibrosis with F508del mutation

When compared with treatment with tezacaftor plus ivacaftor alone, triple combination therapy with elexacaftor/tezacaftor/ivacaftor improved lung function, respiratory-related quality of life and sweat chloride concentrations in patients aged 12 years and older with cystic fibrosis homozygous for the F508del mutation, according to data published in The Lancet.

The findings parallel results from another phase 3 trial comparing elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) with placebo in patients with cystic fibrosis with a single Phe508del allele recently published in The New England Journal of Medicine.

For the phase 3, randomized, double-blind, active-controlled trial, 113 patients underwent a 4-week run-in period during which they all were treated with tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals). Patients were then randomly assigned 4 weeks of treatment with elexacaftor 200 mg once daily in combination with tezacaftor 100 mg once daily and ivacaftor 150 mg every 12 hours (n = 55) or tezacaftor 100 mg once daily plus ivacaftor 150 mg every 12 hours (n = 52) for another 4 weeks.

All patients had cystic fibrosis homozygous for the F508del mutation, stable disease and a percentage of predicted FEV1 of 40% to 90%.

After 4 weeks of treatment, results linked triple therapy, as compared with dual therapy, to significant improvement in the percentage of predicted FEV1 (least squares mean treatment difference, 10 percentage points; P < .0001). Additionally, the researchers noted that sweat chloride concentrations were lower (least squares mean treatment difference, –45.1 mmol/L; P < .0001) and Cystic Fibrosis Questionnaire-Revised respiratory domain scores were better (least squares mean treatment difference, 17.4 points; P < .0001) with triple therapy vs. dual therapy.

Elexacaftor/tezacaftor/ivacaftor also resulted in increases in mean BMI (least squares mean difference, 0.6 kg/m2; nominal P < .0001) and mean body weight (least squares mean difference, 1.6 kg; nominal P < .0001) when compared with tezacaftor/ivacaftor alone.

Adverse events in the triple therapy group were mostly mild or moderate, with serious adverse events occurring in two patients in the triple therapy group and one in the dual therapy group, and no patients discontinued study treatment.

“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 wrote. “This degree of cystic fibrosis transmembrane conductance regulator (CFTR) modulation in such a large proportion of people with cystic fibrosis could profoundly affect the face of cystic fibrosis care.”

The study was limited by its small sample size and short duration, leaving questions about long-term efficacy in terms of pulmonary exacerbations and lung function improvement, Edith T. Zemanick, MD, and Frank J. Accurso, MD, both from the department of pediatrics at the University of Colorado Anschutz Medical Campus in Aurora, noted in a linked comment.

However, they added that the findings are encouraging and open the door to other questions about use of CFTR modulators in this patient population.

“We do not yet understand how improvements in CFTR activity will affect individuals over a lifetime, including those who already have structural lung disease. CFTR modulators have also been studied with background standard-of-care cystic fibrosis therapies (eg, airway clearance regimens), which carry a substantial burden to patients and families. Whether the use of modulators will allow withdrawal from some of these therapies without clinical decline is not known but will be an area of active investigation in the future,” Zemanick and Accurso wrote. “Despite these cautions, the advent of highly effective modulator therapy for people with cystic fibrosis homozygous for F508del offer genuine hope for individuals with cystic fibrosis and their families.” by Melissa Foster

Disclosure s: This study was funded by Vertex Pharmaceuticals. Heijerman reports he has received speaker fees from Chiesi, Horizon Pharma, PTC Therapeutics, TEVA and Vertex and fees for advisory board participation from PTC Therapeutics and Vertex. Please see the study for all other authors’ relevant financial disclosures. Zemanick reports she has served as site principal investigator for several trials funded or sponsored by Vertex Pharmaceuticals and has received grants from the NIH and Cystic Fibrosis Foundation. Accurso reports no relevant financial disclosures.

When compared with treatment with tezacaftor plus ivacaftor alone, triple combination therapy with elexacaftor/tezacaftor/ivacaftor improved lung function, respiratory-related quality of life and sweat chloride concentrations in patients aged 12 years and older with cystic fibrosis homozygous for the F508del mutation, according to data published in The Lancet.

The findings parallel results from another phase 3 trial comparing elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) with placebo in patients with cystic fibrosis with a single Phe508del allele recently published in The New England Journal of Medicine.

For the phase 3, randomized, double-blind, active-controlled trial, 113 patients underwent a 4-week run-in period during which they all were treated with tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals). Patients were then randomly assigned 4 weeks of treatment with elexacaftor 200 mg once daily in combination with tezacaftor 100 mg once daily and ivacaftor 150 mg every 12 hours (n = 55) or tezacaftor 100 mg once daily plus ivacaftor 150 mg every 12 hours (n = 52) for another 4 weeks.

All patients had cystic fibrosis homozygous for the F508del mutation, stable disease and a percentage of predicted FEV1 of 40% to 90%.

After 4 weeks of treatment, results linked triple therapy, as compared with dual therapy, to significant improvement in the percentage of predicted FEV1 (least squares mean treatment difference, 10 percentage points; P < .0001). Additionally, the researchers noted that sweat chloride concentrations were lower (least squares mean treatment difference, –45.1 mmol/L; P < .0001) and Cystic Fibrosis Questionnaire-Revised respiratory domain scores were better (least squares mean treatment difference, 17.4 points; P < .0001) with triple therapy vs. dual therapy.

Elexacaftor/tezacaftor/ivacaftor also resulted in increases in mean BMI (least squares mean difference, 0.6 kg/m2; nominal P < .0001) and mean body weight (least squares mean difference, 1.6 kg; nominal P < .0001) when compared with tezacaftor/ivacaftor alone.

Adverse events in the triple therapy group were mostly mild or moderate, with serious adverse events occurring in two patients in the triple therapy group and one in the dual therapy group, and no patients discontinued study treatment.

“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 wrote. “This degree of cystic fibrosis transmembrane conductance regulator (CFTR) modulation in such a large proportion of people with cystic fibrosis could profoundly affect the face of cystic fibrosis care.”

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The study was limited by its small sample size and short duration, leaving questions about long-term efficacy in terms of pulmonary exacerbations and lung function improvement, Edith T. Zemanick, MD, and Frank J. Accurso, MD, both from the department of pediatrics at the University of Colorado Anschutz Medical Campus in Aurora, noted in a linked comment.

However, they added that the findings are encouraging and open the door to other questions about use of CFTR modulators in this patient population.

“We do not yet understand how improvements in CFTR activity will affect individuals over a lifetime, including those who already have structural lung disease. CFTR modulators have also been studied with background standard-of-care cystic fibrosis therapies (eg, airway clearance regimens), which carry a substantial burden to patients and families. Whether the use of modulators will allow withdrawal from some of these therapies without clinical decline is not known but will be an area of active investigation in the future,” Zemanick and Accurso wrote. “Despite these cautions, the advent of highly effective modulator therapy for people with cystic fibrosis homozygous for F508del offer genuine hope for individuals with cystic fibrosis and their families.” by Melissa Foster

Disclosure s: This study was funded by Vertex Pharmaceuticals. Heijerman reports he has received speaker fees from Chiesi, Horizon Pharma, PTC Therapeutics, TEVA and Vertex and fees for advisory board participation from PTC Therapeutics and Vertex. Please see the study for all other authors’ relevant financial disclosures. Zemanick reports she has served as site principal investigator for several trials funded or sponsored by Vertex Pharmaceuticals and has received grants from the NIH and Cystic Fibrosis Foundation. Accurso reports no relevant financial disclosures.