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Clinical Efficacy and Safety of CFTR-Directed Therapies in Cystic Fibrosis: A Systematic Review and Meta-Analysis
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A6269 - Clinical Efficacy and Safety of CFTR-Directed Therapies in Cystic Fibrosis: A Systematic Review and Meta-Analysis
Author Block: A. Habib1, M. Kajbafzadeh1, C. L. Yang2, K. Skolnik3, B. Quon4; 1Sydney Medical Program, The University of Sydney, Sydney, Australia, 2British Columbia Children's Hospital, Vancouver, AB, Canada, 3Medicine, University of Calgary, calgary, AB, Canada, 4Div of Respirology, Univ of British Columbia, Vancouver, BC, Canada.
Rationale: Several randomized, placebo-controlled clinical trials have been recently published investigating therapies targeting the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein defect responsible for CF. This systematic review examines the clinical efficacy and safety of CFTR-directed therapies in CF patients.
Methods: Medline, EMBASE, the Cochrane Library, and other sources were systematically searched for phase 2 and 3, placebo-controlled, parallel-design clinical trials published in full text investigating gene replacement therapy and CFTR modulators from January 1, 2005 to June 30, 2017. The primary outcome of interest was % predicted FEV1 (ppFEV1). Secondary outcomes included pulmonary exacerbations, hospitalizations, nutritional parameters, respiratory symptoms, sweat chloride results, and adverse events.
Results: Fourteen RCTs met our study eligibility criteria. Improvements in ppFEV1 favouring treatment (vs. placebo) were observed for lumacaftor-ivacaftor (LUMA-IVA) combination therapy in F508del homozygous patients (weighted absolute mean difference 3.2, 95% CI: 2.6 - 3.9) and IVA monotherapy in G551D patients (weighted absolute mean difference 10.6, 95% CI: 9.3 - 11.9). No statistically significant absolute improvements in ppFEV1 were observed for IVA monotherapy in F508del homozygous or R117H patients, LUMA-IVA in F508del heterozygous patients, ataluren in patients with a nonsense mutation, or liposomal gene therapy (pGM169/GL67A) in patients with any genotype. Most of the CFTR-directed therapies were safe except LUMA monotherapy increased the risk of respiratory-related adverse events and ataluren increased the risk of acute kidney injury.
Conclusion: IVA monotherapy in G551D patients and LUMA-IVA in F508del homozygous patients result in significant improvements in ppFEV1 and other important clinical outcomes compared to placebo.
Author Block: A. Habib1, M. Kajbafzadeh1, C. L. Yang2, K. Skolnik3, B. Quon4; 1Sydney Medical Program, The University of Sydney, Sydney, Australia, 2British Columbia Children's Hospital, Vancouver, AB, Canada, 3Medicine, University of Calgary, calgary, AB, Canada, 4Div of Respirology, Univ of British Columbia, Vancouver, BC, Canada.
Rationale: Several randomized, placebo-controlled clinical trials have been recently published investigating therapies targeting the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein defect responsible for CF. This systematic review examines the clinical efficacy and safety of CFTR-directed therapies in CF patients.
Methods: Medline, EMBASE, the Cochrane Library, and other sources were systematically searched for phase 2 and 3, placebo-controlled, parallel-design clinical trials published in full text investigating gene replacement therapy and CFTR modulators from January 1, 2005 to June 30, 2017. The primary outcome of interest was % predicted FEV1 (ppFEV1). Secondary outcomes included pulmonary exacerbations, hospitalizations, nutritional parameters, respiratory symptoms, sweat chloride results, and adverse events.
Results: Fourteen RCTs met our study eligibility criteria. Improvements in ppFEV1 favouring treatment (vs. placebo) were observed for lumacaftor-ivacaftor (LUMA-IVA) combination therapy in F508del homozygous patients (weighted absolute mean difference 3.2, 95% CI: 2.6 - 3.9) and IVA monotherapy in G551D patients (weighted absolute mean difference 10.6, 95% CI: 9.3 - 11.9). No statistically significant absolute improvements in ppFEV1 were observed for IVA monotherapy in F508del homozygous or R117H patients, LUMA-IVA in F508del heterozygous patients, ataluren in patients with a nonsense mutation, or liposomal gene therapy (pGM169/GL67A) in patients with any genotype. Most of the CFTR-directed therapies were safe except LUMA monotherapy increased the risk of respiratory-related adverse events and ataluren increased the risk of acute kidney injury.
Conclusion: IVA monotherapy in G551D patients and LUMA-IVA in F508del homozygous patients result in significant improvements in ppFEV1 and other important clinical outcomes compared to placebo.
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