AstraZeneca asthma drug misses endpoint in phase 3

A phase 3 trial of AstraZeneca’s tralokinumab in patients with severe, uncontrolled asthma has missed its primary endpoint. The anti-interleukin-13 (IL-13) human monoclonal antibody failed to cut the annual asthma exacerbation rate by more than placebo, forcing AstraZeneca to hitch its hopes for the drug to the planned analysis of a subpopulation of patients.

AstraZeneca enrolled more than 1,000 adult and adolescent asthmatics whose condition was poorly controlled by inhaled corticosteroids and long-acting beta2-agonists and randomized them to receive either twice-monthly injections of tralokinumab or a placebo. The trial ran for 52 weeks and assessed the change in asthma exacerbation rates of patients over this period. Tralokinumab failed to outperform the placebo against this primary endpoint.

That setback forced AstraZeneca to look to a planned analysis of a subpopulation of patients with a biomarker status indicative of increased IL-13 activity for a more upbeat reading of the data. In that population, the trial delivered a “clinically relevant” reduction in the rate of exacerbations.

Buoyed by that finding, AstraZeneca plans to make the IL-13 subgroup the focus of its analysis of its second phase 3 trial of tralokinumab. AstraZeneca described the first trial as having “explored the potential to use biomarkers to identify patients with an enhanced response to tralokinumab.” And the second trial as “designed to validate the biomarker population identified” in the first study. Both trials used the same inclusion and exclusion criteria.

Such subpopulation analyses can enable companies to unearth seemingly-positive snippets from otherwise negative data. But in the case of tralokinumab, AstraZeneca has long thought its best shot may lie in patients with increased IL-13 activity.

Back when AstraZeneca decided to move the antibody into phase 3 in 2014, CEO Pascal Soriot said the plan for the respiratory disease pipeline was to target subpopulations of patients who respond to best to different mechanisms such as those featuring IL-5 and IL-13. And in 2015 it teamed up with Abbott to develop a companion diagnostic to spot patients with biomarkers predictive of upregulated IL-13.

AstraZeneca is hoping this more targeted approach can enable it to break the run of late-phase misfires for IL-13 drugs. Roche discontinued development of its IL-13 drug lebrikizumab in asthma after two identical phase 3 trials yielded different results. In one trial the drug succeeded in cutting the rate of severe exacerbations. In the other study it failed against the same endpoint. After sifting through the mixed bag of data, Roche terminated another study in patients with severe corticosteroid-dependent asthma.