[en] BACKGROUND: Interleukin-23 has been implicated in airway inflammation that is mediated by type 2 and type 17 cytokines. Whether targeting interleukin-23 in the treatment of asthma improves disease control and reduces airway inflammation is unclear.
METHODS: We conducted a phase 2a, multicenter, randomized, double-blind, placebo-controlled, 24-week, parallel-group trial to assess the efficacy and safety of risankizumab, an anti-interleukin-23p19 monoclonal antibody, in adults with severe asthma. Patients were assigned to receive 90 mg of risankizumab or placebo, administered subcutaneously once every 4 weeks. The primary end point was the time to the first asthma worsening. Asthma worsening was defined as deterioration from baseline on 2 or more consecutive days; deterioration was considered to be a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in the number of puffs of rescue medication in a 24-hour period (equating to at least four additional puffs), a severe asthma exacerbation, or an increase of 0.75 or more points on the 5-item Asthma Control Questionnaire (ACQ-5; scores range from 0 to 6, with higher scores indicating less control). Secondary end points were the annualized rate of asthma worsening, the annualized rate of severe exacerbations, the ACQ-5 score, and the forced expiratory volume in 1 second. Exploratory end points were assessed with the use of sputum cytologic analysis and gene expression analysis, and safety was assessed.
RESULTS: A total of 105 patients received risankizumab and 109 received placebo. The clinical characteristics of the patients were similar in the two groups. The time to the first asthma worsening was shorter with risankizumab than with placebo (median, 40 days vs. 86 days; hazard ratio, 1.46; 95% confidence interval [CI], 1.05 to 2.04; P = 0.03). The rate ratio for annualized asthma worsening with risankizumab as compared with placebo was 1.49 (95% CI, 1.12 to 1.99), and the rate ratio for severe exacerbations was 1.13 (95% CI, 0.75 to 1.70). Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of the type 1 helper T and type 17 helper T transcription factors were down-regulated by risankizumab. No safety concerns were associated with risankizumab therapy.
CONCLUSIONS: Risankizumab treatment was not beneficial in severe asthma. The time to the first asthma worsening was shorter and the annualized rate of asthma worsening was higher with risankizumab than with placebo. (Funded by AbbVie and Boehringer Ingelheim; ClinicalTrials.gov number, NCT02443298.).
Research Center/Unit :
GIGA I3-Cellular and Molecular Immunology - ULiège
Disciplines :
General & internal medicine
Author, co-author :
Brightling, Christopher E; From the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B., D.J.C.), and the University of Manchester, Manchester University NHS Foundation Trust, Manchester (D.S.) - both in the United Kingdom, the Firestone Institute for Respiratory Health, McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.), and the GIGA-I3 Research Unit, University of Liege, Department of Pneumology, Centre Hospitalier Universitaire Liège, Liege, Belgium (R.L
Nair, Parameswaran; From the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B., D.J.C.), and the University of Manchester, Manchester University NHS Foundation Trust, Manchester (D.S.) - both in the United Kingdom, the Firestone Institute for Respiratory Health, McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.), and the GIGA-I3 Research Unit, University of Liege, Department of Pneumology, Centre Hospitalier Universitaire Liège, Liege, Belgium (R.L
Cousins, David J ; From the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B., D.J.C.), and the University of Manchester, Manchester University NHS Foundation Trust, Manchester (D.S.) - both in the United Kingdom, the Firestone Institute for Respiratory Health, McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.), and the GIGA-I3 Research Unit, University of Liege, Department of Pneumology, Centre Hospitalier Universitaire Liège, Liege, Belgium (R.L
LOUIS, Renaud ; Université de Liège - ULiège > GIGA > GIGA I3 - Pneumology ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Singh, Dave; From the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B., D.J.C.), and the University of Manchester, Manchester University NHS Foundation Trust, Manchester (D.S.) - both in the United Kingdom, the Firestone Institute for Respiratory Health, McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.), and the GIGA-I3 Research Unit, University of Liege, Department of Pneumology, Centre Hospitalier Universitaire Liège, Liege, Belgium (R.L
Language :
English
Title :
Risankizumab in Severe Asthma - A Phase 2a, Placebo-Controlled Trial.
Supported by AbbVie and Boehringer Ingelheim. No authors received direct compensation related to the development of this article. Drs. Brightling, Nair, Louis, and Singh received funding from Boehringer Ingelheim to support the conduct of the trial. Editorial support was provided by MediTech Media, a medical communications company contracted with and fundedby Boehringer Ingelheim. The gene expression analyses were supported in part by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2 JU), under grant agreement number 831434 for Taxonomy, Targets, Treatment, and Remission, and by the Leicester NIHR Biomedical Research Centre and the Manchester NIHR Biomedical Research Centre. IMI 2 JU receives support from the European Union Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. Dr. Louis is supported by a federal Excellence of Science (EOS) grant (30565447) from the govern- ment of Belgium. Dr. Nair is supported by the Frederick E. Har-greave Teva Innovation Chair in Airway Diseases.
Commentary :
Inhibiting Il-23 by rizankizumab results in loss of disease control in severe asthmatics
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