AstraZeneca Announces Positive Phase III ETHOS Trial Results for Breztri Aerosphere in COPD

Today, AstraZeneca announced that its triple-combination therapy Breztri Aerosphere (formerly known as PT010; budesonide/glycopyrronium/formoterol fumarate), comprising a corticosteroid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta2-agonist (LABA), met the primary endpoint in the Phase III ETHOS trial for chronic obstructive pulmonary disease (COPD). Detailed data will be presented at future academic conferences. Both doses of the triple combination demonstrated a greater reduction in the rate of moderate-to-severe exacerbations compared with the existing LAMA/LABA combination Bevespi Aerosphere and the corticosteroid/LABA combination Symbicort. ETHOS is a pivotal trial within the ATHENA program, enrolling 8,500 participants out of the program’s total of 15,000. Breztri Aerosphere was launched in Japan two months ago.

COPD, also known as smoker’s disease, is a highly severe and prevalent condition affecting a vast population. It is estimated that there are over 300 million patients worldwide, with 3 million deaths annually, making it the fifth leading cause of death globally and one of the five common diseases with the highest medical expenditures. As the most common respiratory disease, COPD, combined with asthma which presents similar symptoms, represents a market worth approximately $25 billion. AstraZeneca and GlaxoSmithKline were once major manufacturers of respiratory medications, and Novartis and Boehringer Ingelheim also had blockbuster drugs in this area; however, these companies are gradually exiting this field and shifting their focus toward oncology.

A key reason is that the pathophysiology of COPD is complex, making it extremely difficult to identify drugs capable of reversing or halting disease progression. All currently marketed medications can only alleviate symptoms. The products under development are largely permutations and combinations of drugs with known mechanisms, primarily aimed at improving ease of use and achieving modest improvements in symptom control. Glaxo’s hormonal/LABA combination, Advair, was once the leading COPD medication, with peak sales approaching $8 billion, alongside several other similar combination drugs with sales around $4 billion. However, subsequent combination therapies have increasingly encountered resistance from payers, resulting in market uptake significantly below expectations. Ten years ago, LAMA/LABA combinations were a hot area of development, but several launched drugs failed to meet expectations due to drastic changes in the reimbursement landscape. Glaxo already has a similar triple-drug combination, Trelegy Ellipta, on the market, but its current sales are still lower than those of Advair, whose patent has already expired.

A compelling hard endpoint to persuade payers is reduced mortality. Several years ago, Advair conducted the TORCH clinical trial involving 6,000 patients; although it demonstrated a 17% reduction in mortality risk compared with placebo, this result did not reach statistical significance. In 2015, GSK’s ICS/LABA combination Breo Ellipta missed its primary endpoint in the large-scale SUMMIT trial, which enrolled 16,000 participants, failing to reduce all-cause mortality compared with placebo—a setback that significantly weakened GSK. Trelegy Ellipta demonstrated a 29% reduction in all-cause mortality compared with GSK’s LAMA/LABA combination Anoro Ellipta in a COPD exacerbation trial; however, GSK currently has no clinical trials specifically designed to evaluate the mortality-reducing effects of its triple therapy akin to the SUMMIT trial. AstraZeneca also has no current plans to initiate similar trials but has stated that it may consider this option if the ETHOS data prove sufficiently robust.

Under competitive pressure, diabetes medications were compelled to initiate large-scale cardiovascular outcomes trials (CVOTs) involving more than 10,000 participants, which unexpectedly revealed the efficacy of SGLT2 inhibitors in heart failure and chronic kidney disease (CKD). However, this rare and fortuitous precedent is unlikely to motivate similar trials for COPD drugs, as a SUMMIT-style failure would deal a devastating blow to any manufacturer. Nevertheless, patent-expired Advair remains the primary competitor that all new combination therapies must confront; without robust clinical data, it is difficult to overcome this barrier.

Original Title: Exclusive | AstraZeneca’s Triple-Drug Combination for COPD Meets Phase III Clinical Endpoints