Tralokinumab for the Treatment of Severe, Uncontrolled Asthma: The ATMOSPHERE Clinical Development Program

Abstract

Tralokinumab, a fully human IgG4 monoclonal antibody, specifically neutralizes IL-13. The ATMOSPHERE clinical development program comprised four randomized, placebo-controlled clinical trials and an open-label study that aimed to assess the efficacy and safety of tralokinumab for the treatment of severe, uncontrolled asthma. The two pivotal trials (STRATOS 1 and STRATOS 2; NCT02161757 and NCT02194699) evaluated the efficacy and safety of tralokinumab, with STRATOS 1 identifying a subgroup most likely to demonstrate enhanced response to treatment. Further trials have assessed the ability of tralokinumab to reduce oral corticosteroid use (TROPOS; NCT02281357) and determined its mechanistic effects (MESOS; NCT02449473). An open-label study in Japanese individuals (NCT02902809) assessed the long-term safety and tolerability of tralokinumab in this population.

Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials

“…Both trials employed hierarchical testing strategies to provide strong global control of Type I error; these strategies are described in a separate publication. 18 The statistical methods used to assess the key secondary objectives are provided in the supplementary appendix.…”

“…This consisted of five trials: the pivotal phase 3 clinical trials, STRATOS 1 (NCT02161757) and 2 (NCT02194699); a phase 3 OCS-sparing clinical trial, TROPOS (NCT02281357); a phase 2 mechanistic clinical trial, MESOS (NCT02449473); and an open-label, long-term trial in Japanese participants (NCT02902809). 18 The ATMOSPHERE clinical programme took a novel approach to assessing the efficacy and safety of tralokinumab treatment for severe asthma. Two pivotal phase 3 trials with identical inclusion and exclusion criteria and endpoints (STRATOS 1 and STRATOS 2) were performed in parallel but with staggered analyses.…”

Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma

“…For example, in severe asthma, IL-13 promotes the production of IgE, leading to recruitment of eosinophils and airway remodeling via IL-4R α, IL-13Rα1, and/or IL-4α [ 4 ]. As part of the ATMOSPHERE late-stage clinical development program [ 5 ], tralokinumab was investigated in two pivotal phase III clinical trials, STRATOS 1 and 2 [ 6 , 7 ], for the treatment of severe, uncontrolled asthma. There are safety challenges associated with developing a mAb for clinical use; for example, mAbs may present an immunogenic risk with the potential to induce severe hypersensitivity reactions such as anaphylaxis [ 8 , 9 ].…”

Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma

“…The tralokinumab late-stage clinical development programme in severe, uncontrolled asthma [17] was specifically designed to include two similar pivotal Phase III trials, STRATOS 1 (NCT02161757) and STRATOS 2 (NCT02194699), which were conducted in parallel but with staggered analyses (Fig. 1) [18].…”

“…The candidate biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum DPP-4 concentration, serum periostin concentration and total serum IgE concentration. These biomarkers are all continuous in nature and are either associated with IL-13 activation [19, 20] or with previous successful treatment of asthma with a biologic therapy [17, 21]. IL-13 was not assessed as a biomarker as circulating levels are very low, and when this study was conducted, available immunoassays did not reliably detect this protein [22].…”