Seth Walker1, Patrick Flume2, John McNamara3, Melinda Solomon4, Mark Chilvers5, James Chmiel6, R Scott Harris7, Eric Haseltine8, David Stiles9, Chonghua Li10, Neil Ahluwalia11, Honghong Zhou10, Caroline A Owen12, Gregory Sawicki13. 1. University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children's Hospital, Ste 604, 11100 Euclid Ave, Cleveland, OH, USA. Electronic address: sdw72@case.edu. 2. Medical University of South Carolina, Rutledge Tower, 135 Rutledge Ave, Charleston, SC, USA. Electronic address: flumepa@musc.edu. 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: john.mcnamara@childrensmn.org. 4. The Hospital for Sick Kids, 555 University Ave, Toronto, ON, Canada. Electronic address: melinda.solomon@sickkids.ca. 5. BC Children's Hospital, 4500 Oak St, Vancouver, BC V6H 3N1, Canada. Electronic address: mchilvers@cw.bc.ca. 6. University Hospitals of Cleveland, Cleveland Medical Center, Rainbow Babies and Children's Hospital, Ste 604, 11100 Euclid Ave, Cleveland, OH, USA. Electronic address: jfchmiel@iu.edu. 7. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: r_scott_harris@vrtx.com. 8. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: eric_haseltine@vrtx.com. 9. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: david_stiles@vrtx.com. 10. Formerly of Vertex Pharmaceuticals Incorporated, Boston, MA, USA. 11. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: Neil_Ahluwalia@vrtx.com. 12. Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA, USA. Electronic address: caroline_owen@vrtx.com. 13. Boston Children's Hospital, Harvard Medical School, Department of Pediatrics, 300 Longwood Ave, Boston, MA, USA. Electronic address: Gregory.Sawicki@childrens.harvard.edu.
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.
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.
Authors: Andrea Gramegna; Martina Contarini; Stefano Aliberti; Rosaria Casciaro; Francesco Blasi; Carlo Castellani Journal: Int J Mol Sci Date: 2020-08-16 Impact factor: 5.923
Authors: Lumír Kunovský; Petr Dítě; Petr Jabandžiev; Michal Eid; Karolina Poredská; Jitka Vaculová; Dana Sochorová; Pavel Janeček; Pavla Tesaříková; Martin Blaho; Jan Trna; Jan Hlavsa; Zdeněk Kala Journal: J Clin Med Date: 2021-12-10 Impact factor: 4.241