Tezacaftor 50mg / Ivacaftor 75mg tablets

Abstract Rationale Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2–5 years. Methods In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (−57.9 mmol/L; 95% confidence interval [CI], −61.3 to −54.6; n = 69) and LCI2.5 (−0.83 U; 95% CI, −1.01 to −0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions In this open-label study in children 2–5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).

Abstract licence: CC BY-NC-ND

Background The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis.Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry.We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older.Methods In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively.Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening.They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period.All participants received matching placebo tablets to maintain the treatment blinding.Randomisation was done using an interactive web-response system and stratified by age, FEV 1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103.The primary endpoint for both trials was absolute change in FEV 1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -30 or higher).Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period.Safety was assessed in all participants who received at least one dose of study drug during the treatment period.These trials are registered with ClinicalTrials.gov,NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete.Findings In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196).Median age was 310 years (IQR 226-385), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White.In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284).Median age was 331 years (IQR 245-422), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White.The absolute change in least squares mean FEV 1 % predicted from baseline through week 24 for Trial VX20-121-102 was 05 (SE 03) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 03 (03) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 02 percentage points [95% CI -07 to 11]; p<00001), and for Trial VX20-121-103, was 02 (SE 03) percentage points in the vanzacaftortezacaftor-deutivacaftor group versus 00 (02) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least

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