Tezacaftor/Ivacaftor Has Long-Term Benefit in CF With F508del-CFTR Mutation

A phase 3 trial found tezacaftor/ivacaftor for CF yielded improvements in ppFEV1 and maintained exacerbation rates for up to 216 weeks.

Use of tezacaftor/ivacaftor (TEZ/IVA) was safe and well tolerated after 216 weeks in patients with cystic fibrosis (CF) and an F508del-CF transmembrane conductance regulator (CFTR) mutation, according to phase 3 clinical trial findings published in Journal of Cystic Fibrosis.

Clinical trials have shown that combined use of tezacaftor, a CFTR corrector, and ivacaftor, a CFTR potentiator, is generally safe, well tolerated, and efficacious in those 12 years of age and older who are homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). However, safety and efficacy with long-term use is still being studied.

Researchers for the EXTEND clinical trial (Study 661-110; ClinicalTrials.gov Identifier: NCT02565914), a 3-part, phase 3 study assessing long-term use of TEZ/IVA for CF, previously reported that TEZ/IVA was safe and efficacious for 120 weeks in Part A of the trial. The current study — Part B — assessed this therapy’s efficacy and safety for an additional 96 weeks. The open-label, rollover study was performed at 87 sites in North America, Europe, Israel, and Australia.

Participants in the current study had either completed Part A of the trial or other related TEZ/IVA clinical trials (ClinicalTrials.gov Identifiers: NCT02730208 and NCT03150719) and were at least 12 years of age with an F/F or F/RF genotype. All participants received a TEZ 100-mg/IVA 150-mg fixed-dose combination tablet once per day in the morning and an IVA 150-mg tablet once daily in the evening for 96 weeks.

Safety endpoints were adverse events (AEs), liver function tests, and ophthalmologic examinations. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1), absolute change from baseline in body mass index (BMI), and number of pulmonary exacerbation (PEx) events.

Improvements in ppFEV1 from baseline were maintained in both the F/F and F/RF groups throughout the 96-week TEZ/IVA treatment period, with higher numerical values observed for the F/RF group.

The study had 463 participants who received at least 1 dose of TEZ/IVA (F/F group: n=347; 52.7% male; mean [SD] age 27.7 [10.7] years; F/RF group: n=106; 48.1% male; mean age 35.1 [13.5] years). A total of 427 (92.2%) patients had at least 1 AE, most of which were mild (27.9%) or moderate (51.0%) in severity; severe AEs occurred in 62 (13.4%) participants. The most common AEs included infective PEx of CF (51.6%), cough (24.2%), and nasopharyngitis (19.0%). Serious AEs were observed in 136 (29.4%) participants, with infective PEx (22.2%) and hemoptysis (2.2%) the most common. No deaths occurred in part B, and 4 (0.9%) participants had AEs that led to treatment discontinuation.

Participants in part B had a mean (SD) baseline ppFEV1 of 58.9 (18.8) in the F/F group and 60.8 (14.2) in the F/RF group. The mean (SD) absolute change from baseline in ppFEV1 at week 96 was 1.7 (10.2) in the F/F group (n=132) and 8.3 (8.6) in the F/RF group (n=49). Lung function was maintained for 96 weeks in both groups.

Notably, 248 participants in Part B of the trial discontinued treatment, leaving 215 patients who completed the study.

In an ad hoc analysis of patients in parts A and B, the mean change from baseline in ppFEV1 at week 96 was 2.8 (8.0) and 1.9 (10.6) in parts A and B, respectively, in the F/F group (n = 110), and 8.8 (8.9) and 8.3 (8.8) in parts A and B, respectively, in the F/RF group (n = 44).

The PEx event rate per year with TEZ/IVA for part B was 0.51 in the F/RF group and 0.77 in the F/F group, which was comparable to that in part A. The 2 groups had a gradual increase in absolute change in BMI from baseline in the 96-week treatment period.

Study limitations include the single-arm design, lack of a control group, and a discontinuation rate of 79.8% in part B. In addition, the F/RF genotype group included participants with different residual function mutations, which limited the number of patients with each type of residual function mutation. Furthermore, the population in part B was not identical to that in part A, and so statistical comparisons using all participants in parts A and B were not made.

“Part B of EXTEND represents the longest duration experience of safety and efficacy for TEZ/IVA in a clinical trial to date,” noted the study authors. “Improvements in ppFEV1 from baseline were maintained in both the F/F and F/RF groups throughout the 96-week TEZ/IVA treatment period, with higher numerical values observed for the F/RF group,” they added. “These results further support the long-term safety and efficacy of TEZ/IVA in this patient population,” the investigators concluded.

Disclosure: This research was supported by Vertex Pharmaceuticals Incorporated. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Flume PA, Harris RS, Paz-Diaz H, et al. Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial. J Cyst Fibros. Published online December 27, 2022. doi:10.1016/j.jcf.2022.12.006