An Open-Label Extension (OLE) study of Tezacaftor/Ivacaftor (TEZ/IVA) in patients (PTS) ≥ 12 years with cystic fibrosis (CF) Homozygous for F508DEL-CFTR (F/F) or Heterozygous for F508DEL-CFTR and a residual function mutation (F/RF)

Objectives: TEZ/IVA was efficacious and generally safe and well tolerated in pts ≥ 12 y with F/F or F/RF mutations in pivotal Phase 3 studies. EXTEND, a 96-wk OLE study, assessed the long-term safety, tolerability, and efficacy of TEZ/IVA in pts ≥ 12 y with F/F or F/RF genotypes who completed TEZ/IVA parent studies.

Methods: Pts received TEZ 100 mg qd/IVA 150 mg q12h. The primary endpoint was safety and tolerability. Pts from studies 107 (F/minimal function) and 109 (F/gating or F/R117H) were discontinued (d/c) from EXTEND by the sponsor (N = 253 pts) because these studies did not meet their primary endpoints; these pts contributed to the safety set prior to d/c. Secondary endpoints were change from baseline in ppFEV₁, number of pulmonary exacerbations (PEx), change from baseline in BMI (z score in pts < 20 y), CFQ-R respiratory domain score, weight (z score in pts < 20 y), height z score in pts < 20 y, time to first PEx, and PK. Safety set: all pts who received ≥ 1 dose of TEZ/IVA in EXTEND (N = 1042). Efficacy sets: pts who received ≥ 1 dose of TEZ/IVA and had F/F (N = 459) or F/RF (N = 226) mutations.

Results: Of 1042 pts in the safety set, 253 pts from studies 107 and 109 were d/c by sponsor, 24 of the remaining pts d/c due to adverse events (AEs), 83 of the remaining pts d/c for other reasons, and 682 completed treatment in EXTEND. There were 995 pts (95.5%) who had ≥ 1 treatment-emergent AE (TEAE); most TEAEs were mild or moderate in severity and consistent with manifestations of CF or the known safety profile of TEZ/IVA. Serious TEAEs occurred in 351 pts (33.7%; infective PEx [23.3%], all others in < 3% of pts). There were 22 pts (2.1%) who had TEAEs leading to TEZ/IVA d/c (those in > 2 pts included transaminase [ALT and/or AST] increased [5 pts, 0.5%] and creatine phosphokinase increased [4 pts, 0.4%]). Placebo pts who began TEZ/IVA in EXTEND had improvements in efficacy endpoints consistent with those seen in the parent studies, and improvements seen in TEZ/IVA pts in parent studies were generally maintained in EXTEND.

Conclusions: TEZ/IVA was generally safe and well tolerated for up to 96 wks; no new safety concerns were identified. Improvements across efficacy endpoints were consistent with Phase 3 outcomes and maintained in F/F and F/RF pts.

Table 1 Efficacy Results in F508del/F508del (F/F) Pts and F508del/Residual Function (F/RF) Pts at Wk 96 in EXTEND^a,b

	F/F Pts at Wk 96 (EXTEND)c		F/RF Pts at Wk 96 (EXTEND)c
	Placebo → TEZ/IVA (calculated from EXTEND baseline)	TEZ/IVA → TEZ/IVA (calculated from parent study baseline)	Placebo → TEZ/IVA (calculated from parent study baseline)	IVA → TEZ/IVA (calculated from parent study baseline)	TEZ/IVA → TEZ/IVA (calculated from parent study baseline)
CFQ-R: Cystic Fibrosis Questionnaire-Revised. a Mean nutritional and growth parameters (BMI; weight; and BMI, weight, and height z scores) were maintained over 96 wks. b PK exposures (AUC) of tezacaftor, ivacaftor, and their major metabolites were within the target ranges of those observed in the pivotal studies. c The efficacy sets included pts who rolled over from EVOLVE (F/F, N = 459) or EXPAND (F/RF, N = 226). d Relative change from baseline in ppFEV1 showed similar trends in F/F and F/RF pts. e Pulmonary exacerbation analysis period includes the time that a pt is on active treatment, and begins either in EVOLVE, EXPAND Period 2, or EXTEND, depending on parent study treatment assignment; PEx estimated event rate per year in pts receiving placebo in EVOLVE was 0.99 and in EXPAND was 0.63.
Absolute change in ppFEV1 (95% CI), percentage pointsd	2.1 (0.8, 3.3) n = 187	2.0 (0.7, 3.2) n = 194	4.1 (2.2, 6.0) n = 68	6.7 (4.7, 8.7) n = 61)	7.5 (5.6, 9.4) n = 67
Absolute change in CFQ-R respiratory domain score (95% CI), points	1.7 (− 0.6, 4.0) n = 196	3.0 (0.7, 5.3) n = 208	10.3 (7.0, 13.6) n = 74	11.2 (7.7, 14.7) n = 65	13.8 (10.3, 17.2) n = 68
Absolute change in BMI (95% CI), kg/m²	0.47 (0.30, 0.65) n = 195	0.38 (0.20, 0.55) n = 208	1.07 (0.59, 1.55) n = 75	0.96 (0.45, 1.47) n = 65	1.05 (0.56, 1.55) n = 68
Estimated PEx event rate per year (95% CI)e	0.68 (0.55, 0.83) n = 231	0.76 (0.63, 0.92) n = 248	0.44 (0.29, 0.66) n = 81	0.28 (0.18, 0.44) n = 74	0.22 (0.14, 0.35) n = 78