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Publications

Journal Article Clinical Trial, Phase III Multicenter Study Ppublish

PubMed: 41837895 DOI: 10.1093/annalsats/aaoag053

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in adolescents and adults with cystic fibrosis and F508del-gating and F508del-residual function genotypes: results from an open-label extension study.

Ann Am Thorac Soc 23(9):1286-1295

Authors: James F Chmiel, Kimberly McBennett, Bradley S Quon, Carla Colombo, Elke De Wachter, Isabelle Fajac, Pedro Mondejar-Lopez, Deepika Polineni, Philip Robinson, Sivagurunathan Sutharsan, Marcus A Mall, Edward F McKone, Bonnie Ramsey, Jennifer L Taylor-Cousar, Elizabeth Tullis, Nina E Suresh, Yaohua Zhang, Patrick Sosnay, Mark Jennings, Peter J Barry

Affiliations

  • Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, United States.
  • University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
  • St. Paul's Hospital, Vancouver, BC, Canada.
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
  • Univeritair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
  • APHP-Université Paris Cité, Paris, France.
  • Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
  • Washington University in St Louis, St Louis, MO, United States.
  • Department of Pediatrics, University of Melbourne, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Essen, Germany.
  • Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • German Center for Child and Adolescent Health (DZKJ), partner site, Berlin, Germany.
  • German Center for Lung Research (DZL), associated partner site Berlin, Berlin, Germany.
  • St Vincent's University Hospital, Dublin, Ireland.
  • Seattle Children's Hospital, Seattle, WA, United States.
  • National Jewish Health, Denver, CO, United States.
  • St Michael's Hospital, Toronto, ON, Canada.
  • Vertex Pharmaceuticals Incorporated, Boston, MA, United States.
  • Manchester University NHS Foundation Trust, Manchester, United Kingdom.
  • Division of Infection, Immunity, and Respiratory Medicine, University of Manchester, Manchester, United Kingdom.

Abstract

RATIONALE

In an 8-week, active-controlled, phase 3 study (445-104), elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in participants ≥ 12 years of age with cystic fibrosis (CF) and F508del-gating (F/G) or F508del-residual function (F/RF) genotypes, conferring additional clinical benefits relative to IVA and TEZ/IVA. Participants who completed this 8-week parent study continued to an open-label extension.

OBJECTIVE

To assess the long-term safety and efficacy of ELX/TEZ/IVA in adolescents and adults with CF and F/G or F/RF genotypes.

METHODS

This 2-part (Part A [96 weeks] and Part B [48 weeks]) phase 3 open-label extension study enrolled adolescents and adults age ≥ 12 years with CF and F/G or F/RF genotypes who completed study 445-104. Primary endpoint (Part A and Part B) was safety and tolerability. Secondary endpoints (Part A only) included absolute changes in percent predicted FEV1 (ppFEV1), sweat chloride concentration, CF Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI).

RESULTS

A total of 251 participants received ≥ 1 dose of ELX/TEZ/IVA in Part A; 217 (86.5%) completed treatment. In Part A, 96.0% of participants had ≥ 1 adverse event (AE), which for most were mild (32.3%) or moderate (55.0%) in severity. Thirteen participants (5.2%) discontinued due to treatment-emergent AEs. Participants who received ELX/TEZ/IVA in the parent study maintained improvements in ppFEV1, sweat chloride concentration, CFQ-R respiratory domain score, and BMI while participants who received IVA or TEZ/IVA (active controls) in parent study had similar improvements after transitioning to ELX/TEZ/IVA. Eighty-four participants (33.5%) entered Part B, 96.4% of whom discontinued due to commercial drug availability. In Part B, 62 participants (73.8%) had ≥ 1 AE, which for most were mild or moderate in severity and none of which led to discontinuation.

CONCLUSIONS

ELX/TEZ/IVA remained generally safe and well-tolerated with no new safety findings. Improvements in lung function, CFTR function, respiratory symptoms, and nutritional status after starting ELX/TEZ/IVA were maintained through 96 weeks of follow-up. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in adolescents and adults with F/G or F/RF genotypes.

MeSH

Safety, Fibrosis, Cystic Fibrosis, Adolescent, Genotype, Therapeutics