Pneumologie 2018; 72(S 01): S35
DOI: 10.1055/s-0037-1619210
Sektion 7 – Klinische Pneumologie
Posterbegehung – Titel: Asthma II und Mukoviszidose
Georg Thieme Verlag KG Stuttgart · New York

Efficacy and Safety of Tezacaftor/Ivacaftor in Patients (Pts) Aged >= 12 Years With CF Heterozygous for F508del and a Residual Function Mutation: A Randomized, Double-blind, Placebo-controlled, Crossover Phase 3 Study

R Fischer
1   Mukoviszidose-Zentrum München-West, Munich
,
SM Rowe
2   University of Alabama, Birmingham, Al, USA
,
JC Davies
3   Imperial College London, South Kensington Campus, UK
,
N Nair
4   Vertex Pharmaceuticals Incorporated, MA, USA
,
L Han
4   Vertex Pharmaceuticals Incorporated, MA, USA
,
J Lekstrom-Himes
4   Vertex Pharmaceuticals Incorporated, MA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
21 February 2018 (online)

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Objectives:

To evaluate efficacy and safety of tezacaftor (VX-661)/ivacaftor (IVA) combination therapy (TEZ/IVA) and IVA monotherapy in pts aged ≥12yrs with CF heterozygous for F508del and a residual function CFTR mutation.

Methods:

This phase 3 crossover trial (NCT02392234) included two 8-wk treatment periods (T1, T2), separated by an 8-wk washout. Pts were randomized to 1 of 6 treatment sequences (T1-T2: TEZ/IVA-IVA; IVA-TEZ/IVA; TEZ/IVA-placebo [PBO]; PBO-TEZ/IVA; IVA-PBO; PBO-IVA) and received TEZ 100 mg qd/IVA 150 mg q12h, IVA 150 mg q12h, or PBO. The primary endpoint was absolute change in ppFEV1; the key secondary endpoint was change in CFQ-R respiratory domain score. All changes were from baseline to the average of wk 4 and wk 8 measurements in both T1 and T2. Safety was a secondary objective.

Results:

Pts received TEZ/IVA (n = 161), IVA (n = 156), or PBO (n = 161). Baseline characteristics were balanced among groups. Significant treatment effects were observed for TEZ/IVA (6.8% points [95% CI: 5.7, 7.8]; P< 0.0001) and IVA (4.7% points [3.7, 5.8]; P< 0.0001) in absolute ppFEV1 vs. PBO. The treatment difference of absolute ppFEV1 between TEZ/IVA and IVA was also statistically significant in favor of TEZ/IVA (2.1% points [1.2, 2.9]; P< 0.0001). Significant treatment effects were also observed for CFQ-R respiratory domain score for TEZ/IVA (11.1 [8.7, 13.6]; P< 0.0001) and IVA (9.7 [7.2, 12.2]; P< 0.0001) vs. PBO. Most adverse events (AEs) were mild (TEZ/IVA 35.8%; IVA 35.0%; PBO 38.9%) or moderate (34.0%; 32.5%; 33.3%). The most common AEs (≥10%) were infective pulmonary exacerbation of CF, cough, headache, and hemoptysis. No increase in abnormal respiration was observed with TEZ/IVA. No treatment discontinuations due to AEs occurred with TEZ/IVA vs. 1.3% with IVA and 0.6% with PBO. Serious AEs were reported (TEZ/IVA 4.9%; IVA 6.4%; PBO 8.6%). No deaths occurred.

Conclusions:

Significant improvements in ppFEV1 and CFQ-R respiratory domain score were seen with TEZ/IVA and IVA vs. PBO. Significant improvement in ppFEV1 was also seen with TEZ/IVA vs. IVA. Treatments were well tolerated with no (TEZ/IVA) or few (IVA) discontinuations due to AEs. These findings support efficacy and safety of TEZ/IVA and IVA in pts with CF heterozygous for F508del and a second mutation resulting in CFTR residual function.