PMID- 37945033 OWN - NLM STAT- MEDLINE DCOM- 20240104 LR - 20240321 IS - 1399-3003 (Electronic) IS - 0903-1936 (Print) IS - 0903-1936 (Linking) VI - 62 IP - 6 DP - 2023 Dec TI - Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study. LID - 10.1183/13993003.02029-2022 [doi] LID - 2202029 AB - BACKGROUND: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) >/=12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV(1)) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV(1) % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA. CI - Copyright (c)The authors 2023. FAU - Daines, Cori L AU - Daines CL AD - University of Arizona, Banner University Medical Center, Tucson, AZ, USA cdaines@arizona.edu. AD - C.L. Daines and E. Tullis contributed equally to this work. FAU - Tullis, Elizabeth AU - Tullis E AD - St Michael's Hospital, Toronto, ON, Canada. AD - C.L. Daines and E. Tullis contributed equally to this work. FAU - Costa, Stefano AU - Costa S AD - University of Messina, Messina, Italy. FAU - Linnemann, Rachel W AU - Linnemann RW AUID- ORCID: 0000-0002-6839-0936 AD - Emory University, Atlanta, GA, USA. FAU - Mall, Marcus A AU - Mall MA AUID- ORCID: 0000-0002-4057-2199 AD - Charite - Universitatsmedizin Berlin, Berlin, Germany. AD - Berlin Institute of Health, Berlin, Germany. AD - German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany. FAU - McKone, Edward F AU - McKone EF AD - St Vincent's University Hospital, Dublin, Ireland. FAU - Polineni, Deepika AU - Polineni D AD - Washington University in St Louis, St Louis, MO, USA. FAU - Quon, Bradley S AU - Quon BS AD - UBC and St Paul's Hospital, Vancouver, BC, Canada. FAU - Ringshausen, Felix C AU - Ringshausen FC AUID- ORCID: 0000-0001-9084-4968 AD - Hannover Medical School and German Center for Lung Research (DZL), Hannover, Germany. AD - European Reference Network Respiratory Diseases (ERN-LUNG), Frankfurt/Main, Germany. FAU - Rowe, Steven M AU - Rowe SM AD - University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Selvadurai, Hiran AU - Selvadurai H AD - The Children's Hospital at Westmead, Westmead, Australia. FAU - Taylor-Cousar, Jennifer L AU - Taylor-Cousar JL AUID- ORCID: 0000-0002-5436-9722 AD - National Jewish Health, Denver, CO, USA. FAU - Withers, Nicholas J AU - Withers NJ AD - Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. FAU - Ahluwalia, Neil AU - Ahluwalia N AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Moskowitz, Samuel M AU - Moskowitz SM AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Prieto-Centurion, Valentin AU - Prieto-Centurion V AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Tan, Yaoyuan Vincent AU - Tan YV AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Tian, Simon AU - Tian S AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Weinstock, Tanya AU - Weinstock T AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Xuan, Fengjuan AU - Xuan F AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Zhang, Yaohua AU - Zhang Y AD - Vertex Pharmaceuticals Incorporated, Boston, MA, USA. FAU - Ramsey, Bonnie AU - Ramsey B AD - Seattle Children's Hospital, Seattle, WA, USA. AD - B. Ramsey and M. Griese contributed equally to this work. FAU - Griese, Matthias AU - Griese M AUID- ORCID: 0000-0003-0113-912X AD - Ludwig Maximilian University and German Center for Lung Research (DZL), Munich, Germany. AD - B. Ramsey and M. Griese contributed equally to this work. CN - VX17-445-105 Study Group LA - eng GR - P30 DK072482/DK/NIDDK NIH HHS/United States GR - P30 DK089507/DK/NIDDK NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article DEP - 20231207 PL - England TA - Eur Respir J JT - The European respiratory journal JID - 8803460 RN - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) RN - RRN67GMB0V (elexacaftor) RN - 1Y740ILL1Z (ivacaftor) RN - 0 (tezacaftor) SB - IM CIN - Eur Respir J. 2023 Dec 7;62(6):. PMID: 38061794 MH - Humans MH - Alleles MH - *Cystic Fibrosis/drug therapy/genetics MH - Cystic Fibrosis Transmembrane Conductance Regulator/genetics MH - Mutation PMC - PMC10701091 COIS- Conflicts of interest: All authors received nonfinancial support (assistance with manuscript preparation) from Nucleus Global, which received funding from Vertex Pharmaceuticals Incorporated. C.L. Daines has nothing further to disclose. E. Tullis has received consulting, speaker and travel fees from Vertex Pharmaceuticals. S. Costa serves on an advisory board for Vertex Pharmaceuticals. R.W. Linnemann serves on an advisory board and reports grants paid to her institution and consulting fees from Vertex Pharmaceuticals. M.A. Mall reports patient recruitment fees paid to his institution and advisory fees from Vertex Pharmaceuticals, consulting fees from Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Santhera, Sterna Biologicals and Vertex Pharmaceuticals, speaker fees from Arrowhead Pharmaceuticals, Boehringer Ingelheim and Vertex Pharmaceuticals, travel fees from Boehringer Ingelheim and Vertex Pharmaceuticals, advisory fees from Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Santhera and Vertex Pharmaceuticals, and serves on the European Cystic Fibrosis Society (ECFS) board. E.F. McKone reports grants, lecture fees and serving on an advisory board for Vertex Pharmaceuticals, lecture fees from Roche, travel fees from A. Menarini, and serving on advisory boards for Janssen, Insmed and CF Storm. D. Polineni reports grants from Laurent Pharmaceuticals, Parion Sciences, Proteostasis Therapeutics and Vertex Pharmaceuticals, consulting fees from Vertex Pharmaceuticals, nonfinancial support for travel to investigator meeting from Vertex Pharmaceuticals, and serves on an advisory board for Sanofi. B.S. Quon reports payments paid to his institution and speaker fees from Vertex Pharmaceuticals. F.C. Ringshausen reports grants paid to his institution from Basilea Pharmaceutica, German Center for Lung Research (DZL), German Center for Infection Research (DZIF), Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis (iABC)/Innovative Medicines Initiative (IMI), European Federation of Pharmaceutical Industries and Associations (EFPIA), Insmed, Novartis and Polyphor, consulting fees from Grifols, Insmed, Parion, Shionogi and Zambon, speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Grifols, Insmed and Novartis, participation on advisory boards for Grifols, Insmed, Parion, Shionogi and Zambon, unpaid honoraria as co-chair of the German Bronchiectasis Registry (PROGNOSIS), and payments to his institution from AbbVie, AstraZeneca, Boehringer Ingelheim, Corbus, Celtaxsys, Insmed, Novartis, Parion, Polyphor, Vertex and Zambon; and is a steering committee member of the European Bronchiectasis Registry (EMBARC), a steering committee member of the European NTM registry (EMBARC-NTM), a core network lead in ERN-LUNG, a principal investigator for DZL, a chair of the cystic fibrosis working group of the German Respiratory Society (DGP), a steering committee member of the Group of German CF Physicians (AGAM), and co-chair of medical consultants of PCD Patient Advocacy Group (Kartagener Syndrom und Primare Ciliare Dyskinesie eV). S.M. Rowe reports grants paid to his institution from AbbVie, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Celtaxsys, Eloxx, Ionis Pharmaceuticals, Novartis, Proteostasis Therapeutics, Synedgen, Synspira Therapeutics, Translate Bio and Vertex Pharmaceuticals, nonfinancial support from AbbVie, Ionis Pharmaceuticals, Proteostasis Therapeutics, Renovion, Synedgen and Synspira Therapeutics, consulting fees from AbbVie, Arrowhead Pharmaceuticals, Bayer, Cystetic Medicines, Ionis Pharmaceuticals, Novartis, Renovion, Synedgen, Synspira Therapeutics and Vertex Pharmaceuticals, and serves as co-chair for the Next Generation Steering Committee on Vertex Pharmaceuticals. H. Selvadurai has nothing further to disclose. J.L. Taylor-Cousar serves on the board of trustees, clinical research executive committee, clinical research advisory board and Women's Health Research-Working Group for the US Cystic Fibrosis Foundation, serves on the scientific advisory board for Emily's Entourage, serves on the respiratory health awards working group, scientific grants review committee and clinical problems assembly programming committee for the American Thoracic Society; reports consulting fees from 4D Molecular Therapeutics, Celtaxsys, Prolarean Imaging, Protalix Biotherapeutics, Proteostasis Therapeutics and Santhera Pharmaceuticals, grants to her institution from Bayer, Celtaxsys, Eloxx Pharmaceuticals, Gilead, N30 and Proteostasis Therapeutics, speaking fees from Celtaxsys and Gilead, serves on advisory board for AbbVie, Genentech, Insmed and Novartis, and is an associate editor for the Journal of Cystic Fibrosis. N.J. Withers reports lecture fees from Vertex Pharmaceuticals and serves on an advisory board for Vertex Pharmaceuticals and Proteostasis Therapeutics. B. Ramsey reports travel fees and grants from, and serves on advisory board for Vertex Pharmaceuticals, and personal fees from Cystetic Medicines. M. Griese reports grants to his institution from Vertex Pharmaceuticals. N. Ahluwalia, S.M. Moskowitz, V. Prieto-Centurion, Y.V. Tan, S. Tian, T. Weinstock, F. Xuan and Y. Zhang are employees of Vertex and may own stock or stock options in Vertex. EDAT- 2023/11/10 00:44 MHDA- 2023/12/17 13:19 PMCR- 2023/12/07 CRDT- 2023/11/09 20:43 PHST- 2022/10/19 00:00 [received] PHST- 2023/09/27 00:00 [accepted] PHST- 2023/12/17 13:19 [medline] PHST- 2023/11/10 00:44 [pubmed] PHST- 2023/11/09 20:43 [entrez] PHST- 2023/12/07 00:00 [pmc-release] AID - 13993003.02029-2022 [pii] AID - ERJ-02029-2022 [pii] AID - 10.1183/13993003.02029-2022 [doi] PST - epublish SO - Eur Respir J. 2023 Dec 7;62(6):2202029. doi: 10.1183/13993003.02029-2022. Print 2023 Dec.