Though patients had a clinically meaningful increase in pre-bronchodilator FEV1, they did not evidence a significantly improved annualized asthma exacerbation rates compared with placebo.
Reynold Panettieri, MD
Tralokinumab, a human monoclonal antibody targeting interleukin 13 (IL-13), did not reduce exacerbations of severe asthma in pivotal phase 3 trials, despite the trials identifying a potentially predictive biomarker and testing the agent in participants most likely to respond.
The recently published STRATOS 1 and STRATOS 2 trials of AstraZeneca’s tralokinumab for severe, uncontrolled asthma were conducted after phase 2 trials yielded only equivocal results, with the strategy of identifying biomarkers of response in the first trial and selecting biomarker-positive subpopulations in the second.
Joint lead authors Reynold Panettieri, MD, Rutgers Institute for Translational Medicine and Science and Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ and Christopher Brightling, PhD, University of Leicester, Leicester, UK, and colleagues noted that animal model studies have evidenced a role of IL-13 in the pathophysiology of asthma, and explained their rationale for pursuing phase 3 clinical investigations of an agent to block its action.
"Subsequent (to preclinical studies) clinical trials have supported a role for interleukin 13 in asthma, with bronchial biopsy samples showing an increased concentration of interleukin 13 in participants with both atopic and non-atopic disease, compared with healthy individuals,” researchers wrote. “Therefore, anti-interleukin-13 agents might have clinical utility for treatment of severe asthma.”
In commentary accompanying the study findings, Kian Fan Chung, National Heart and Lung Institute, Imperial College London, UK, suggested that while there was an improved measure of forced expiratory volume in 1 second (FEV1) in the ostensibly more responsive subpopulation, the study results indicated that an anti-IL-13 approach is “unlikely to be of significant clinical benefit for patients with severe uncontrolled asthma."
In the staggered 1-year trials, 1207 participants with severe, uncontrolled asthma in STRATOS 1 and 856 in STRATOS 2 received placebo or tralokinumab subcutaneously every 2 or 4 weeks (in STRATOS 1) and every 2 weeks (in STRATOS 2) as add-on therapy to ongoing treatment with inhaled corticosteroid and long-acting beta adrenergic bronchodilator. The primary efficacy measure in both trials was reduction in annualized asthma exacerbation rate (AAER).
Of 5 potential biomarkers of increased IL-13, all associated with type 2 inflammation, baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1. FENO-high participants receiving tralokinumab every 2 weeks (n= 97) in STRATOS 1 evidenced 44% reduced AAER compared with placebo.
Although that population had a clinically meaningful increase in pre-bronchodilator FEV1 in STRATOS 2, they did not evidence a significantly improved AAER compared with placebo.
Panettieri, Brightling and colleagues noted that similar results were obtained in phase 3 trials with lebrikizumab (Tanox), another monoclonal antibody targeting IL-13, with improved FEV1 but without reduction in asthma exacerbations.
"Taken together, these clinical data suggest that drugs targeting the interleukin 13 pathway affect airway smooth muscle tone, which is consistent with previous preclinical data suggesting that interleukin 13 promotes airway hyper-responsiveness and smooth muscle contractility," researchers wrote.
The investigators, and Chung point out that the results with tralokinumab contrast with the reduction in asthma exacerbations that has been evidenced with dupilumab (Dupixent), which affects both IL-4 and IL-13.
"Integration of these results with those reported with the anti-interleukin-13 antibody therapies might suggest that there may be synergistic interactions between interleukin 4 and interleukin 13," Chung wrote.
The study, "Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials," was published online in The Lancet Respiratory Medicine.