The long-awaited arrival of fixed-dose, triple therapy for chronic obstructive pulmonary disease (COPD) tops the recent advances in the treatment of the disease, but questions remain about which patients will benefit most and whether some might be harmed.
GlaxoSmithKline’s once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol combination Trelegy Ellipta became the first and only available fixed-dose, triple therapy for COPD in the U.S. when it was approved by the FDA in September 2017.
It was initially approved for the treatment of COPD patients with bronchitis and/or emphysema whose disease is not adequately controlled by the fixed-dose combination of fluticasone furoate and vilanterol or for patients already receiving umeclidinium and a fixed-dose combination of fluticasone furoate and vilanterol.
Early in 2018, the indication for use was expanded to include a broader population of COPD patients, and the FDA is currently considering applications for approval of several other fixed-dose, single-inhaler, triple therapies that combine a long-acting β-agonist (LABA), long-acting muscarinic-receptor antagonists (LAMA), and inhaled corticosteroid (ICS).
Phase III results from the KRONOS trial, reported at the European Respiratory Society (ERS) International Congress in Paris last September, showed treatment with the fixed-dose combination of budesonide, glycopyrrolate, and formoterol in a metered-dose inhaler (MDI) to be associated with improved lung function and reduced exacerbations.
In the AstraZeneca-sponsored trial, treatment for 24 weeks with the investigational triple therapy was associated with a significant 52% reduction in the rate of moderate to severe COPD exacerbations compared with treatment with the combination of glycopyrrolate/formoterol fumarate (AstraZeneca’s drug Bevespi).
In February 2018, results from the TRIBUTE trial showed Chiesi Farmaceutici’s fixed-dose, triple therapy to reduce exacerbation risk compared with dual LAMA/LABA therapy in COPD patients with severe airflow restrictions and a history of exacerbations.
Pneumonia Signal Limits Use of Triple Therapy
Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment guidelines, last updated in 2017, recommend escalation to triple therapy only after maximized bronchodilator treatment with LAMA/LABA regimens in patients with symptomatic GOLD group D COPD with frequent exacerbations, due to safety concerns including the risk of pneumonia associated with adding ICS to LABA/LAMA treatment.
GlaxoSmithKline’s IMPACT trial, reported in the New England Journal of Medicine (NEJM) in April 2018, included more than 10,000 patients with COPD. Patients treated for a year with once-daily, inhaled Trelegy Ellipta had significantly lower rates of moderate or severe COPD and fewer exacerbations, compared with dual, long-acting bronchodilator therapy regardless of patient blood eosinophil count.
The pneumonia rate was more than 50% higher in the patients receiving the triple therapy than in patients receiving the LABA/LAMA combination, however.
In an accompanying editorial, “Making Sense of Triple Inhaled Therapy for COPD,” NEJM editor-in-chief Jeffrey Drazen, MD, and Samy Suissa, PhD, of McGill University in Montreal, wrote that the inclusion of patients already taking inhaled glucocorticosteroids, some of whom had a history of asthma, may have inflated the benefits of triple therapy over dual bronchodilator treatment.
Drazen and Suissa wrote that “until further evidence is available,” clinicians should rely on the updated GOLD guidelines and limit triple therapy to patients with GOLD group D COPD with frequent exacerbations.
“Although single-inhaler triple therapy offers simplicity in treating COPD, any potential benefit could be lost and potential undue harm induced if triple therapy is expanded to patients with GOLD groups A, B, and C COPD,” the editorial stated.
KRONOS trial researcher Gary Ferguson, MD, who presented the study findings at the ERS congress, told MedPage Today at the time that the trials could change how physicians are treating patients in the near future, with triple therapy considered an option for patients with moderate-to-severe COPD without an elevated risk for exacerbations.
Ferguson said he believes the results of KRONOS, but also the TRIBUTE, IMPACT, and SUNSET trial results, could change how physicians are treating patients a year or two down the road, with triple therapy considered an option for moderate-to-severe COPD patients at lower risk of exacerbations.
In the SUNSET study, reported in May 2018 at the annual meeting of the American Thoracic Society (ATS), COPD patients without a high eosinophil burden who were doing well on triple therapy had no increase in exacerbations when switched to step-down treatment with the dual-bronchodilator therapy indacaterol/glycopyrronium (Ultibro Breezhaler).
Patients in the study with consistent blood eosinophil counts of 300 μl or above, however, showed significant declines in lung function and increased risk for exacerbation on the fixed-dose dual therapy, suggesting they are more likely to benefit from continued triple therapy.
The study, funded by Novartis, was the first to evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to the once-daily LABA/LAMA treatment in patients with moderate-to-severe COPD who do not have frequent exacerbations.
FDA Rejects Biologic Nucala for COPD
In an interview with MedPage Today, COPD researcher and pulmonary specialist James F. Donohue, MD, of the University of North Carolina at Chapel Hill, said that while it is increasingly clear that COPD patients with a history of exacerbations and hospitalizations should be offered triple therapy, there remains a great deal of controversy about the role of peripheral blood eosinophil count as a biomarker of disease severity and for identifying patients most likely to benefit from ICS treatment.
“I think at this point most people would accept that patients with blood eosinophil counts over 300 are candidates for triple therapy,” Donohue said, adding that some studies suggest that a count as low as 150 cells/μL is indicative of an eosinophilic COPD phenotype.
He pointed out that GlaxoSmithKline defined eosinophilic COPD as having blood eosinophil counts of 150 cells/μL or higher in two pivotal trials of its biologic mepolizumab (Nucala) for the treatment of COPD. Mepolizumab is approved for the treatment of eosinophilic asthma.
Last fall, the FDA rejected the company’s application for approval as an add-on therapy to inhaled ICS for patients with eosinophilic phenotype COPD, after an advisory panel overwhelmingly recommended against approval. During a day-long hearing, FDA reviewers repeatedly raised questions about the clinical relevance of the eosinophilic phenotype in COPD and the absence of an agreed-upon cutoff to define patients with the phenotype.