FDA advisory panel does not back mortality risk-reduction update to Trelegy Ellipta label

The FDA Pulmonary-Allergy Drugs Advisory Committee voted 14-1 against a proposed labeling claim that Trelegy Ellipta reduces all-cause mortality in patients with COPD.

The committee’s vote came after presentations and discussion of Trelegy Ellipta (GlaxoSmithKline) and supporting trial results. The company’s request to update the label to include data on reduction in risk of all-cause mortality in patients with COPD was based on data from the IMPACT trial. During the discussion, the committee members largely agreed that the IMPACT trial did not provide substantial evidence to support the proposed claim for the labeling update.

Trelegy Ellipta is a once-daily single-inhaler triple therapy that contains fluticasone furoate, an inhaled corticosteroid; umeclidinium, a long-acting muscarinic antagonist; and vilanterol, a long-acting beta2-adrenergic agonist. It was approved in 2017 for long-term, once-daily maintenance treatment of patients with COPD.

The discussion focused on the pivotal, randomized, double-blind, parallel-group IMPACT trial that evaluated Trelegy Ellipta (fluticasone furoate 100 g, umeclidinium 62.5 g and vilanterol 25 g) vs. dual therapy (umeclidinium and vilanterol; Anoro Ellipta, GlaxoSmithKline) in 10,355 patients with moderate-to-severe COPD for 52 weeks.

Results demonstrated a 34% reduction in severe COPD exacerbations with Trelegy Ellipta vs. dual therapy (0.13 vs. 0.19 per year; P < .001). Trelegy Ellipta also resulted in significant and clinically meaningful reductions in the annual rate of on-treatment moderate-to-severe COPD exacerbations.

For all-cause mortality, a predefined exploratory endpoint, the IMPACT trial demonstrated a 28% reduction in risk for mortality with Trelegy Ellipta vs. dual therapy (HR = 0.72; 95% CI, 0.53-0.99; P = .042).

“In my view, the presentation failed to adequately demonstrate the difference in survival in the triple therapy group versus the [dual therapy] group,” panel member Scott E. Evans, MD, FCCP, ATSF, professor in the department of pulmonary medicine in the division of internal medicine at The University of Texas MD Anderson Cancer Center, Houston, said following the vote.

The committee also discussed two other trials that assessed all-cause mortality in COPD as primary endpoint and compared them with the IMPACT trial. The SUMMIT and TORCH trials had all-cause mortality evaluation as the primary objective with longer trial durations (1.8 years and 3 years). Both trials recruited different patient populations with COPD than IMPACT; SUMMIT focused on less-severe and better-controlled COPD and TORCH focused on moderate-to-very-severe COPD and did not require a history of previous COPD exacerbations.

Also discussed, the design of the IMPACT trial combined the addition of inhaled corticosteroids (ICS) and removal of ICS. IMPACT mandated the continuation of pre-study ICS during the run-in period and then participants were randomly assigned to two different arms with ICS and one without.

The FDA committee questioned whether pre-study ICS use and ICS removal in the IMPACT trial had on effect on outcomes. Compared with 71% of patients enrolled in IMPACT on pre-study inhaled corticosteroids, one third of patients enrolled in SUMMIT and about half of the patients enrolled in TORCH used pre-study inhaled corticosteroids.

“There are enough unanswered questions here that I don’t think having this in the label —the implication of this for most clinicians of wanting to put a patient on this medicine to reduce their patients’ chance of dying — I don’t think we have the information to support that conclusion,” panel member John M. Kelso, MD, staff physician in the division of allergy, asthma and immunology at Scripps Clinic, San Diego, said during the meeting.

Currently, there are no FDA-approved drugs for COPD management or treatment that improve all-cause mortality.

“The IMPACT trial demonstrated that [Trelegy Ellipta] reduced severe exacerbations and, so, in a disease like this, that’s clearly enough for the FDA to approve this drug,” panel member Susan S. Ellenberg, MD, professor of biostatistics and interim chair in the department of biostatistics, epidemiology and informatics and professor of medical ethics and health policy at Perelman School of Medicine at the University of Pennsylvania, Philadelphia, said during the discussion. “I’m not sure how critical it is to show that there’s a survival benefit. In a disease like this, if you are improving people’s quality of life, in some cases perhaps even with a slight reduction in survival ... that’s worthwhile.”

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does.

References:

• FDA briefing information. Available at: https://www.fda.gov/media/141585/download. Accessed August 31, 2020.
• GSK briefing information. Available at: https://www.fda.gov/media/141587/download. Accessed August 31, 2020.