A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis

Seth Walker; Patrick Flume; John McNamara; Melinda Solomon; Mark Chilvers; James Chmiel; R Scott Harris; Eric Haseltine; David Stiles; Chonghua Li; Neil Ahluwalia; Honghong Zhou; Caroline A Owen; Gregory Sawicki; VX15-661-113 Investigator Group

doi:10.1016/j.jcf.2019.06.009

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis

J Cyst Fibros. 2019 Sep;18(5):708-713. doi: 10.1016/j.jcf.2019.06.009. Epub 2019 Jun 26.

Authors

Affiliations

¹ University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children's Hospital, Ste 604, 11100 Euclid Ave, Cleveland, OH, USA. Electronic address: [email protected].
² Medical University of South Carolina, Rutledge Tower, 135 Rutledge Ave, Charleston, SC, USA. Electronic address: [email protected].
³ Children's Respiratory and Critical Care Specialists, Children's Hospitals and Clinics of Minnesota, 2530 Chicago Ave S, Ste 400, Minneapolis, MN, USA. Electronic address: [email protected].
⁴ The Hospital for Sick Kids, 555 University Ave, Toronto, ON, Canada. Electronic address: [email protected].
⁵ BC Children's Hospital, 4500 Oak St, Vancouver, BC V6H 3N1, Canada. Electronic address: [email protected].
⁶ University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children's Hospital, Ste 604, 11100 Euclid Ave, Cleveland, OH, USA. Electronic address: [email protected].
⁷ Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: [email protected].
⁸ Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: [email protected].
⁹ Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: [email protected].
¹⁰ Formerly of Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
¹¹ Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: [email protected].
¹² Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: [email protected].
¹³ Boston Children's Hospital, Harvard Medical School, Department of Pediatrics, 300 Longwood Ave, Boston, MA, USA. Electronic address: [email protected].

PMID: 31253540
DOI: 10.1016/j.jcf.2019.06.009

Abstract

Background: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations.

Methods: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV₁), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score.

Results: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV₁ remained stable in the normal range, and growth parameters remained stable over 24 weeks.

Conclusions: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

Keywords: Cystic fibrosis; Ivacaftor; Tezacaftor.

Publication types

Clinical Trial, Phase III
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aminophenols* / administration & dosage
Aminophenols* / adverse effects
Aminophenols* / pharmacokinetics
Benzodioxoles* / administration & dosage
Benzodioxoles* / adverse effects
Benzodioxoles* / pharmacokinetics
Biological Availability
Child
Child, Preschool
Chloride Channel Agonists / administration & dosage
Chloride Channel Agonists / adverse effects
Chloride Channel Agonists / pharmacokinetics
Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
Cystic Fibrosis* / diagnosis
Cystic Fibrosis* / drug therapy
Cystic Fibrosis* / genetics
Dose-Response Relationship, Drug
Drug Monitoring / methods
Drug Therapy, Combination / methods
Female
Humans
Indoles* / administration & dosage
Indoles* / adverse effects
Indoles* / pharmacokinetics
Male
Mutation
Quinolones* / administration & dosage
Quinolones* / adverse effects
Quinolones* / pharmacokinetics
Respiratory Function Tests / methods*
Sweat* / chemistry
Sweat* / drug effects
Treatment Outcome

Substances

Aminophenols
Benzodioxoles
Chloride Channel Agonists
Indoles
Quinolones
tezacaftor
Cystic Fibrosis Transmembrane Conductance Regulator
ivacaftor

Associated data

ClinicalTrials.gov/NCT02953314