Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis

Figures & data

Table 1 Classes of CFTR mutations

Class	Type of defect	Examples of mutation
Class I	Defective protein synthesis	G542X, W1282X, R553X
Class II	Defective protein processing	F508del, N1303K
Class III	Defective protein regulation	G178R, S549N, G551D, G551S
Class IV	Defective protein conductance	R117H, R334W, R347P
Class V	Reduced protein synthesis	3849+10kbC→T, 2789+5G→A, 3120+1G→A
Class VI	Accelerated CFTR turnover	Q1412X

Notes: CFTR mutations can be divided into six functional classes. Class I mutations result in no protein production. Class II mutations cause defective protein folding and processing. Class III mutations affect channel regulation. Class IV mutations cause reduced conduction. Class V mutations cause a substantial reduction in mRNA or protein, or both, Class VI mutations cause substantial plasma membrane instability.

Table 2 Clinical trials of ivacaftor monotherapy in CF

Reference	Study design	Results
Ramsey et al.^Citation15 STRIVE	Placebo controlled, double-blind, parallel study. Population:  ● G551D mutation in at least one allele  ● Age≥12  ● ppFEV1 40–90% Duration: 48 weeks Open-Label, rollover study (PERSIST [17]), 96 weeks	10.6 percentage points improvement in absolute ppFEV1, 55% reduction in pulmonary exacerbation rate, 48 mmol/L drop in sweat chloride, 2.7 kg weight gain
Davies et al.^Citation16 ENVISION	Placebo controlled, double-blind, parallel study. Population:  ● G551D in at least one allele  ● Age 6–11 years.  ● ppFEV1 40–105% Duration: 48 weeks Open-Label, rollover study (PERSIST),^Citation17 96 weeks	10 percentage points adjusted absolute FEV1 improvement, 53 mmol/L drop in sweat chloride 2.8 kg weight gain

Notes: The study design and main results of clinical trials of ivacaftor monotherapy are summarized in the table. ppFEV1 is the percentage of predicted FEV1 at screening.

Table 3 Clinical trials of lumacaftor and ivacaftor combination therapy in CF

Reference	Study design	Results
Wainwright et al.^Citation25 TRAFFIC/ TRANSPORT	Two Phase III, randomized, Placebo controlled, double-blind studies Combined lumacaftor (600 mg qd or 400 mg q12h) with ivacaftor (250 mg q12h) or matched placebo Population:  ● Phe508del homozygous  ● Age ≥12  ● ppFEV1 40–90%  ● Number: 1,108 Duration: 24 weeks	2.6–4 percentage points improvement in absolute ppFEV1; 30–39% reduction in pulmonary exacerbations
Konstan et al.^Citation26 PROGRESS	Phase III extension study of patients who completed TRAFFIC or TRANSPORT Parallel group, multicenter study Duration: 96 weeks	Patients on combination therapy had a 42% slower rate of ppFEV1 decline compared to matched registry control. Long-term safety of combination therapy: consistent with previous randomized control trials.

Notes: The study design and main results of clinical trials of lumacaftor/ivacaftor combination therapy are summarized in the table. ppFEV1 is the percentage of predicted FEV1 at screening.

Table 4 Clinical trials of tezacaftor and ivacaftor combination therapy in CF

Reference	Study design	Results
Taylor‑Cousar et al.^Citation30 EVOLVE	Phase III, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial. Population:  ● F508del homozygous  ● Age≥12  ● ppFEV1 40–90% Duration: 24 weeks	510 randomized; 475 completed trial 4 percentage points improvement in absolute ppFEV1 35% reduction in annual pulmonary exacerbation rate No significant difference in BMI 10.1 mmol/L drop in sweat chloride level No significant safety concerns
Rowe et al.^Citation31 EXPAND	Phase III, randomized, double-blind, placebo-controlled, crossover trial Population:  ● F508del heterozygous (with a CFTR mutation associated with residual CFTR function)  ● Age≥12  ● ppFEV1 40–90% Duration: two 8 weeks intervention, separated by 8 week wash out	248 randomized; 234 completed the two intervention periods; 481 evaluable periods 6.8 and 4.7 percentage points improvement in absolute ppFEV1 for tezacaftor/ivacaftor and ivacaftor monotherapy, respectively, 9.5 and 4.5 mmol/L drop in sweat chloride level for tezacaftor/ivacaftor and ivacaftor monotherapy, respectively No significant safety concerns

Notes: Summary of Phase-III clinical studies evaluating tezacaftor/ivacaftor combination therapy in patients with CF. The dosage of tezacaftor/ivacaftor was 100 mg o.d. and 150 mg 12 hourly, respectively. In the EXPAND trial tezacaftor/ivacaftor combination therapy, ivacaftor monotherapy or placebo were the interventions. ppFEV1 is the percentage of predicted FEV1 at screening.

Table 5 Clinical trials of next-generation corrector, tezacaftor and ivacaftor combination therapy in CF

Reference	Study design	Results
Davies et al.^Citation32	Phase II, randomized, double-blind, multicenter, placebo or active-controlled. Combination: VX-659–tezacaftor–ivacaftor Population:  ● F508del homozygous (placebo comparator)  ● Or F508del/MF heterozygous (placebo/tezacaftor/ivacaftor comparator)  ● Age≥18  ● ppFEV1 40–90% Duration: 4 weeks	117 randomized; 115 completed trial 9.7 percentage points improvement in absolute ppFEV1 in the homozygous population 10.2 to 13.3 percentage points improvement in absolute ppFEV1 in the heterozygous population 42.2 mmol/L drop in sweat chloride level in the homozygous population 43.8 to 51.4 mmol/L drop in sweat chloride level in the heterozygous population 19.5 points improvement in the CFQ-R respiratory domain score in the homozygous population 19.8 to 24.6 points improvement in the CFQ-R respiratory domain score in the heterozygous population No significant safety concerns
Keating et al.^Citation33	Phase II, randomized, double-blind, multicenter, placebo or active-controlled. Combination: VX-445–tezacaftor–ivacaftor Population:  ● F508del homozygous (placebo comparator)  ● Or F508del/MF heterozygous(placebo/tezacaftor/ivacaftor comparator)  ● Age≥18  ● ppFEV1 40–90% Duration: 4 weeks	123 randomized; 119 completed trial 11 percentage points improvement in absolute ppFEV1 in the homozygous population 7.9 to 13.8 percentage points improvement in absolute ppFEV1 in the heterozygous population 39.6 mmol/L drop in sweat chloride level in the homozygous population 33.8 to 39.1 mmol/L drop in sweat chloride level in the heterozygous population 20.7 points improvement in the CFQ-R respiratory domain score in the homozygous population 15.4 to 25.7 points improvement in the CFQ-R respiratory domain score in the heterozygous population No significant safety concerns

Notes: Summary of phase-clinical studies evaluating next-generation correctors (VX-659 and VX-445) in combination with tezacaftor/ivacaftor in patients with CF. The dosage of tezacaftor/ivacaftor was 100 mg o.d. and 150 mg 12 hourly, respectively. Varying doses of next-generation correctors were used. VX-651, a deuterated form of ivacaftor which is dosed once a day, was also evaluated instead of ivacaftor. The results with VX-651 were similar. ppFEV1 is the percentage of predicted FEV1 at screening.

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