Amgen and AstraZeneca announced results from the PATHWAY Phase 2b trial of tezepelumab that showed a significant reduction in the annual asthma exacerbation rate compared with placebo in patients with severe, uncontrolled asthma. Tezepelumab is a novel anti-thymic stromal lymphopoietin (TSLP) monoclonal antibody being developed by MedImmune, AstraZeneca's global biologics research and development arm, in collaboration with Amgen.
The trial results have been published in the New England Journal of Medicine (NEJM), and will be followed by an oral presentation at the European Respiratory Society (ERS) International Congress 2017 in Milan on Sept. 12, 2017.
The PATHWAY trial achieved its primary efficacy endpoint, showing annual asthma exacerbation rate reductions of 61 percent, 71 percent and 66 percent in the tezepelumab arms receiving either 70 mg or 210 mg every four weeks or 280 mg every two weeks, respectively (p<0.001 for all comparisons to placebo). In the trial, tezepelumab was given as an add-on therapy to patients with a history of asthma exacerbations and uncontrolled asthma despite receiving inhaled corticosteroids/long-acting beta-agonists with or without oral corticosteroids (OCS) and additional asthma controllers.
Significant and clinically meaningful reductions in the exacerbation rate were observed independent of baseline blood eosinophil count or other type 2 inflammatory biomarkers. Tezepelumab also demonstrated improvements in lung function at all doses and in asthma control at the two higher doses (p<0.05 for all comparisons to placebo). The incidence of adverse events was similar between the tezepelumab and placebo groups. The most common adverse events (≥5 percent) in tezepelumab-treated patients were asthma, nasopharyngitis, headaches and bronchitis.2 Future studies in large populations of patients will be important in confirming the results demonstrated in this trial.
"These efficacy results confirm the hypothesis that TSLP is an important mediator of inflammation in severe asthma," said Jonathan Corren, M.D., David Geffen School of Medicine, UCLA and Principal Investigator of the PATHWAY trial. "Due to its activity early in the inflammatory cascade, tezepelumab may be suitable for patients with both T2 and non-T2 driven asthma, including those ineligible for current biologic therapies which only target the T2 pathway."
TSLP is an upstream epithelial cytokine that drives multiple inflammatory pathways in various diseases, including asthma. TSLP is active in the regulation of T2 immunity; however, it may also play a role in non-T2 driven inflammation by activating or signaling to many types of cells, such as mast cells, basophils, natural killer T cells, innate lymphoid cells and neutrophils. Therefore, TSLP has been identified as a potential therapeutic target across a broad asthma population.
Asthma affects 315 million individuals worldwide, and up to 10 percent of asthma patients have severe asthma, which may be uncontrolled despite high doses of standard of care asthma controller medicines and can require the use of chronic OCS.
Severe, uncontrolled asthma is debilitating, with patients experiencing frequent exacerbations and significant limitations on lung function.
T2 inflammation-driven (T2 high) asthma is present in more than two-thirds of patients with severe asthma and is typically characterized by elevated levels of T2 inflammatory biomarkers, including blood eosinophils, serum IgE and fractional exhaled nitric oxide (FeNO). Conversely, approximately one-third of patients with severe asthma do not present with features of an activated T2 inflammatory pathway, and no biologic treatment options currently exist for these patients whose non-T2 driven disease is uncontrolled on established standard of care therapies.
Tezepelumab is a human anti-TSLP monoclonal antibody that is designed to specifically bind to human TSLP and prevent interaction with its receptor complex. Blocking TSLP with tezepelumab may prevent the release of pro-inflammatory cytokines by immune cells targeted by TSLP. Due to its activity early in the inflammation cascade, tezepelumab may be suitable for a broad population of patients with severe, uncontrolled asthma, including in those whose asthma is not T2 driven.