Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR

Abstract

Rationale: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor.

Objectives: To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D.

Methods: This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day).

Measurements and main results: Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV₁ (ppFEV₁) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV₁ in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV₁ in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all).

Conclusions: These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

Keywords: CFTR modulator; cystic fibrosis transmembrane conductance regulator corrector; forced expiratory volume; sweat chloride.

Figure 1.

Study design. ^aStudy arm analyzed in both the dose escalation and dosage regimen testing phases. ^bFive subjects counted in both pooled placebo groups. q12h = every 12 hours; qday = every day.

Figure 2.

Subject disposition. (A and B) Disposition of subjects homozygous for F508del-pooled groups in (A) the dose escalation phase and (B) the alternative dosage regimen testing phase; and (C) disposition of subjects compound heterozygous for F508del and G551D. Figure E1 (see the online supplement) provides more detail on each study arm. ^aFive subjects were counted in both pooled placebo groups. ^bSeventeen subjects who received tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) were counted in both the dose escalation and dosage regimen testing phases.

Figure 3.

Efficacy in subjects homozygous for F508del in the dose escalation phase. (A) Change in sweat chloride and (B) absolute change in ppFEV₁ from baseline through Day 28. Subjects in the combination therapy arms were treated with ivacaftor at 150 mg every 12 hours. *P < 0.05 versus baseline within group; ^†P < 0.05 versus placebo; P values only reported for tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) and tezacaftor (150 mg every day)/ivacaftor (150 mg every 12 h). CI = confidence interval; LS = least squares; ppFEV₁ = percent predicted FEV₁; qday = every day.

Figure 4.

Efficacy of combination treatment in subjects homozygous for F508del during the dose escalation phase. (A) Mean absolute changes in ppFEV₁ for the treatment and washout periods for tezacaftor plus ivacaftor (150 mg every 12 h) in the dose escalation phase; and individual subject absolute changes in ppFEV₁ at Day 28 for the (B) tezacaftor (100 mg every day) plus ivacaftor (150 mg every 12 h) cohort and (C) placebo cohort. Analysis of change from baseline at all measurements up to Day 28 was based on a mixed-effect model for repeated measures. For the washout period, summary statistics are shown. LS = least squares; ppFEV₁ = percent predicted FEV₁; q12h = every 12 hours; qday = every day.

Figure 5.

Efficacy in subjects homozygous for F508del in the dosage regimen testing phase. (A) Change in sweat chloride and (B) absolute change in ppFEV₁ from baseline through Day 28. ^aSubjects also analyzed in the dose escalation phase. ^bComparison versus placebo not calculated. *P < 0.05 versus baseline within group; P values reported only for tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h). CI = confidence interval; LS = least squares; ppFEV₁ = percent predicted FEV₁; q12h = every 12 hours; qday = every day.

Figure 6.

Efficacy in subjects compound heterozygous for F508del and G551D who received combination therapy. (A) Change in sweat chloride and (B) absolute change in ppFEV₁ from baseline through Day 28. *P < 0.05 versus baseline within group; ^†P < 0.05 versus placebo through Day 28. CI = confidence interval; LS = least squares; ppFEV₁ = percent predicted FEV₁; q12h = every 12 hours; qday = every day.