Attendees at the American Thoracic Society 2018 International Conference, meeting in San Diego, California, heard details that led to FDA's recent expansion of the indication for GlaxoSmithKline's Trelegy Ellipta, including findings that the once-daily combination also provides significant mortality benefits over a dual therapy that is often the combination patients with chronic obstructive pulmonary disease (COPD) are taking when triple therapy is recommended.
Last month, FDA expanded the indication for GlaxoSmithKline’s Trelegy Ellipta, a triple therapy for chronic obstructive pulmonary disease (COPD) given by a single inhaler, based on results from the phase 3 IMPACT trial published in the New England Journal of Medicine (NEJM).1,2
On Sunday, attendees at the American Thoracic Society 2018 International Conference, meeting in San Diego, California, heard details on those results, including findings that the once-daily combination also provides significant mortality benefits over a dual therapy that is often the combination patients with COPD are taking when triple therapy is recommended.3
David Lipson, MD, director of Clinical Drug Discovery for GlaxoSmithKline and lead author of the study, presented both sets of results at a session on the changing role of inhaled corticosteroids in treatment of COPD. He said IMPACT was designed to evaluate the risk and benefits and of triple therapy and to identify which patients are best suited for it, since this has been a source of some controversy in the field.
Lipson described a unique study design that did not have patients slowly taper off existing therapies before being randomized on either triple therapy or 1 of 2 dual therapy combinations. "That's not what happens in real life," he said.
As authors noted in the NEJM article, IMPACT sought to add evidence where it was lacking: the study addressed how much patients with the most severe COPD symptoms benefit from the use of single inhalers that combine the inhaled glucocorticoid fluticasone furoate (FF) with umeclidinium (UMEC), a long-acting muscarinic antagonist (LAMA); and vilanterol (VI), a long-acting beta2-adrenergic agonist (LABA). Some COPD patients with severe symptoms were already using all 3 therapies with multiple inhalers.
Findings from the study of 10,355 patients showed statistically significant reductions in the primary endpoint: the annual rate of moderate and severe exacerbations. There was a 15% reduction when triple therapy was compared with FF/VI, (0.91 annual exacerbation rate for triple therapy, compared with 1.07 for FF/VI, P <.001) and a 25% reduction when triple therapy was compared with the LAMA/LABA combo, UMEC/VI (a 1.21 annual exacerbation rate, P <.001).2
Researchers also found that users of the single inhaler triple therapy had lower annual rates of hospitalization for severe exacerbations: the rate was 0.13 for triple therapy; 0.15 for FF/VI, for 13% reduction, which was not significant; and 0.19 for UMEC/VI, for a 34% reduction, which was significant. In his talk, Lipson noted the difference in the overall annual rates of hospitalization compared with time to first exacerbation between triple therapy and UMEC/VI (the difference was 16%); it appears the benefit of the inhaled corticosteroid increases over time, he said.
Also, the findings showed that patients who began treatment with the highest levels of white blood cells called eosinophils benefited the most from triple therapy, and these may become an important biomarker in determining who should get treatment. Lipson said work in ongoing to determine the right "cut point" at which eosinophil levels call for triple therapy.
Results of the second abstract showed that study patients taking triple therapy experienced a 5.5% reduction in risk of all-cause mortality compared with the FF/VI patients (95% CI, -40.2% to 36.3%; P = .780), and a 42.1% reduction in risk compared with the UMEC/VI (LAMA/LABA) patients (95% CI, 11.9% to 61.9%; P = .011).
However, researchers reported higher rates of pneumonia for patients with triple therapy (hazard ratio, 1.53; 95% confidence interval [CI], 1.22 to 1.92; P <.001). An accompanying editorial in NEJM said while the IMPACT trial’s key strength is its comparison with the LAMA/LABA combination, the rate of pneumonia among patients on triple therapy was 50% higher than those in the LAMA/LABA group. The editorial said the study design posed interpretation challenges, because patients assigned to the LAMA/LABA group who were already taking a glucocorticoid were abruptly withdrawn from that drug, which could have affected the results.4 But in his presentation, Lipson pointed out that the overall number of pneumonia cases was quite low, and was far offset by the number of exacerbations that were prevented.
A member of the audience commented that the editorial should have noted the mortality benefit, to laughter from others. Lipson replied that he preferred to let "the data speak for themselves."
Trelegy Ellipta was first approved in September 2017 for patients with a history of exacerbations who were taking the FF/VI combination or all 3 therapies through multiple inhalers. The expanded indication announced April 24, 2018, means the therapy can be used to treat COPD patients with airflow limitation or who have experienced a worsening of respiratory symptoms.1
According to CDC data, total US medical costs from COPD were $32.1 billion in 2010 and are expected to rise to $49 billion by 2020. Of the 2010 medical costs, 18% was paid for by private insurance, 51% by Medicare, and 25% by Medicaid.5
GlaxoSmithKline funded the study.