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Tralokinumab: Astrazeneca’s Road to Failure

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Tralokinumab: AstraZeneca’s Road to Failure

Abstract:

Tralokinumab (CAT-354) is a fully human monoclonal antibody that binds to and prevents the inflammatory cytokine IL-13 from binding to its signaling counterparts IL-13Rα1 and IL-13Rα2, thus inhibiting IL-13 signaling. Since aberrant IL-13 signaling has been shown to be a driving factor of pathogenesis in both inflammatory and chronic diseases, AstraZeneca began conducting preclinical studies with Tralokinumab that resulted in the antibody proceeding to clinical trials in humans for the treatment of ulcerative colitis, idiopathic pulmonary fibrosis, and severe uncontrolled asthma. The drug failed to reach its primary efficacy endpoints in phase II clinical trials treating ulcerative colitis and idiopathic pulmonary fibrosis, thus ending the company’s development of the drug for those indications. AstraZeneca then made a costly mistake when they proceeded into phase III clinical trials developing the drug to treat severe, uncontrolled asthma and failed to meet primary endpoints in three separate trials. The company has discontinued development of the drug for the aforementioned indications, but did attempt to rescue some of the financial loss from the drug’s failure by selling the rights to the drug for dermatological uses to LEO Pharma in July 2016.

Background:

Many diseases involving chronic, inflammatory, maladaptive host immune system responses have a complex pathogenesis caused by a mixture of environmental and genetic factors that lead to the heterogeneous activation of disease-related signaling pathways. Finding targets to treat such diseases has proven to be very difficult due to the lack of knowledge concerning precise disease causation, the complexity and overlap found in associated signaling pathways, and the heterogeneous nature of the diseases within the human population. Some recent attempts to develop new drugs to treat these types of diseases have involved targeting cytokines known to mediate key pathogenic processes, in hopes that the treatment will have clinically relevant effects. Tralokinumab (CAT-354) is an example of an attempt by AstraZeneca to develop a drug targeting the pleiotropic cytokine IL-13 for the treatment of severe, uncontrolled asthma and other possible indications such as ulcerative colitis (UC) and idiopathic pulmonary fibrosis (IPF).

IL-13 is a Th2-type cytokine that is mainly secreted by CD4+ Th2 effector cells involved in the induction of a humoral immune response, but also secreted by other cell types such as dendritic cells. IL-13 mediates its effects through binding its receptor (a heterodimer complex composed of IL-13Rα1, and IL-4Rα) expressed on almost all cell types and initiating signal transduction cascades that induce gene expression changes in the cell. Some of the known effector functions of IL-13 are mediation of allergic asthma, regulation of eosinophilic inflammation, upregulation of mucus secretion, stimulation of airway hyper-responsiveness (AHR), mediation of tissue fibrosis, and regulation of IgE synthesis through induction of activated B cells9. Tralokinumab is a fully human IL-13 neutralizing IgG4 monoclonal antibody that sterically prevents IL-13 from binding IL-13Rα1 and IL-13Rα2 and thus inhibits formation of the tertiary complex responsible for signaling between IL-13 and its receptors IL-13Rα1, and IL-4Rα. Due to its novel binding region on IL-13, it also inhibits signaling through IL13Rα2, known as the decoy receptor, which may be involved in the mediation of fibrosis and thus may have additional clinical benefit over the other available IL-13 neutralizers such as Lebrikizumab13.

Preclinical Development:

AstraZeneca began the preclinical development of Tralokinumab for the treatment of severe, uncontrolled asthma based on previous research done concerning asthma pathogenesis indicating that IL-13 signaling stimulated many processes involving the central features of asthma such as activation and recruitment of inflammatory cells, stimulation of AHR by activating airway smooth muscle cells, and mediation of airway structural changes such as tissue fibrosis and mucus hypersecretion. IL-13 mRNA and protein levels are elevated in bronchial fluid and tissue from asthmatics compared to control subjects and IL-13 expression in the lung is correlated with the control and severity of asthma in humans. Data from animal models of asthma also suggest that IL-13 may be a key mediator in asthma pathogenesis, with administration of recombinant IL-13 to allergen-naïve mice and selective IL-13 overexpression in transgenic mice both resulting in an asthmatic phenotype9.

In vitro studies using a human pre-myeloid erythroleukemic cell line and a human umbilical vein endothelial cell line assessed the potency and selectivity of Tralokinumab, which was found to be both highly potent (165 pM affinity for human IL-13) and highly selective for human IL-13 not showing any reactivity with non-human IL-13 or IL-4 (a structurally similar cytokine). In vitro studies also assessed the drug’s effect on key disease mechanisms, the results of which will be discussed below along with results from in vivo studies. In vivo studies were conducted using three different animal models to facilitate preclinical pharmacology testing with the highly human IL-13 specific antibody. The approaches included use of recombinant human IL-13 to activate mouse IL-13 receptors, and allergen challenge models in humanized mice and cynomolgus monkeys9.

Based on previous research the development of AHR and airflow limitation appears to be the most asthma-relevant effects of IL-13. In vitro, Tralokinumab prevented the potentiation of bronchial smooth muscle calcium signaling responses induced by IL-13 supporting role of IL-13 in modulating airway smooth muscle contractility. In vivo, drug treatment prevented the development of AHR during antigen challenge in both mouse models used and prevented the recapitulation of AHR in cynomolgus monkeys undergoing antigen challenge, supporting a key role for IL-13 in AHR development. In vitro results supported an anti-eosinophilic effect of IL-13 neutralization in the lung; however, these results were not supported with any significance in the in vivo studies using animal models. The results of in vitro and in vivo studies also did not show support for the role of IgE axis modulation and potential reduction in serum IgE levels from IL-13 neutralization, which is the mechanism by which the only new asthma treatment of the last decade works to help severe asthmatics regain control of the disease. Limitations of the preclinical study include the challenge in finding animal models of asthma that have significant relevance to the disease processes in humans. Further, the humanization of IL-13 altered the biology of the IL-13 axis in mice limiting the quality of data derived from these studies. The use of several types of animal models attempted to increase the reliability and translatability of Tralokinumab treatment effects to asthmatic disease processes in humans. Taken together, these results suggest that Tralokinumab may produce clinically relevant results in humans to alleviate the symptoms of AHR in asthma through the inhibition of a novel pathway of allergic inflammation9.

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