FDA Panel Votes Against Recommending Mepolizumab for COPD

Troy Brown, RN

July 26, 2018

The US Food and Drug Administration's (FDA's) Pulmonary-Allergy Drugs Advisory Committee voted overwhelmingly not to recommend (no-16, yes-3) mepolizumab (Nucala, GlaxoSmithKline) "as add-on treatment to inhaled corticosteroid-based maintenance treatment for the reduction of exacerbations in patients with chronic obstructive pulmonary disease (COPD) guided by blood eosinophil counts."

Mepolizumab is a monoclonal antibody that decreases eosinophil maturation and survival by binding to interleukin-5 (IL5) and preventing it from interacting with the IL5 receptor. The FDA approved mepolizumab for severe asthma with eosinophilic phenotype on November 4, 2015, and for eosinophilic granulomatosis with polyangiitis on December 13, 2017. Mepolizumab is given subcutaneously (SC) at a dose of 100 mg.

In both disorders, eosinophil levels are often elevated, but the involvement of eosinophils in COPD is less clear. The panel was asked to discuss the role of eosinophils in a subtype of patients with COPD.

The panel's vote followed discussion of safety and efficacy data from two phase 3 clinical trials, MEA117106 (study 106) and MEA117113 (study 113), both of which were multinational, randomized, double-blind, placebo-controlled trials that lasted 52 weeks. The studies included patients with COPD who were also receiving triple therapy with inhaled corticosteroids, a long-acting beta agonist, and a long-acting muscarinic antagonist. The primary efficacy endpoint in both studies was the rate of moderate to severe exacerbation of COPD at 52 weeks.

Study 106 included 836 patients with a wide range of eosinophil counts. The researchers stratified patients by high and low eosinophil counts but focused their primary analysis on the high-eosinophil stratum (≥150 cells/μL at screening or ≥300 cells/μL in the prior 12 months). The study randomly assigned 417 patients to receive mepolizumab 100 mg every 4 weeks and 419 patients to receive placebo.

The researchers based peripheral blood eosinophil count criteria upon those used in the severe asthma development program.

Study 113 included only patients in the high-eosinophil stratum. It randomly assigned 674 patients to receive mepolizumab 100 mg SC every 4 weeks (n = 223), mepolizumab 300 mg SC every 4 weeks (n = 225), or placebo (n = 226).

Efficacy

The committee voted 3 to 16 against the drug's efficacy for the proposed indication.

"I think we need more data and perhaps a third trial to really define with more robustness whether this is a real improvement or not, and I would advocate that, clearly, any next trial should be certain the patients are really optimally using their inhaled drugs, with the thought that perhaps we're missing something and having to reach for something else to help them," temporary voting panel member Erik R. Swenson, MD, professor of medicine, physiology, and biophysics, University of Washington, Seattle, said of his vote against mepolizumab's efficacy.

In study 106, patients in the high-eosinophil stratum who received mepolizumab experienced a statistically significant decrease in the rate of moderate to severe COPD exacerbations compared with patients in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 - 0.98; P = .04).

Among those in the low-stratum group, there was a numerical rise in the rate of exacerbations in patients in the 100-mg group (rate ratio, 1.23; 95% CI, 0.99 - 1.51). This "raises concerns about accurately defining the COPD population for mepolizumab use," the FDA notes in its briefing document.

In study 113, moderate to severe COPD exacerbations were not significantly reduced in patients in either mepolizumab group after adjusting for multiplicity: mepolizumab 100 mg SC every 4 weeks (rate ratio, 0.80; 95% CI, 0.65 - 0.98; P = .07) or 300 mg SC every 4 weeks (rate ratio, 0.86; 95% CI, 0.7 - 1.05; P = .1).

No dose response was seen between the 100-mg and 300-mg dose groups; however, the 100-mg dose was associated with a consistent reduction in exacerbation rate across the studies.

Certain key endpoints, including time to first moderate to severe COPD exacerbation, demonstrated numerical trends that favored mepolizumab; however, the researchers found no consistent and clinically meaningful differences in severe COPD exacerbation rate, forced expiratory volume in 1 second, or responses to St. George's Respiratory Questionnaire between patients who received mepolizumab 100 mg and those who received placebo.

"Coming from the world of cystic fibrosis, I want to see studies that show strong trends, have logic, and this seems to fall into that category, and for patients that have no other options, it's one step forward," committee chairperson and voting member Jeffrey S. Wagener, MD, professor emeritus, Department of Pediatrics, University of Colorado Medical School, Aurora, said of his vote in favor of the drug's efficacy.

Safety

The panel voted 17 to 2 that the safety data are adequate to recommend approval of mepolizumab for this indication.

The FDA allowed the researchers to conduct a pooled analysis of safety data from the two pivotal trials, as the trials were similarly designed and the randomly assigned populations were comparable.

A total of 865 patients received any dose of mepolizumab; 645 received placebo. Deaths were similar between those in the mepolizumab group and the placebo group.

Overall, for patients in the mepolizumab and placebo groups, the number of on-treatment serious adverse events (SAEs), as well as the exposure-adjusted rate of such events, were similar.

For some adverse events (AEs) and SAEs, rates were higher among those in the mepolizumab groups compared with those who received placebo. The FDA briefing document said imbalances in cardiovascular SAEs, including supraventricular tachyarrhythmias and cardiovascular thrombotic events, were "noteworthy."

Adverse reactions that were experienced by more than 2.5% of those who received mepolizumab and that occurred more often than in the placebo groups included back pain, cough, oropharyngeal pain, diarrhea, sinusitis, bronchitis, extremity pain, nausea, hypertension, constipation, oral candidiasis, fatigue, and contusion.

Treatment-emergent AEs that occurred in 1% or more of those in the mepolizumab groups and that occurred at least twice as frequently than in patients who received placebo included rhinorrhea, nasal congestion, herpes zoster, rash, conjunctivitis, and elevations in C-reactive protein levels.

"I agree that there was not a big signal for adverse events, but it's also a small population that does not have a lot of women or minorities," voting committee member Carrie A. Redlich, MD, MPH, professor of medicine, pulmonary section, and occupational and environmental medicine and director, Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, Connecticut, said of her vote against the drug's safety.

Concern About Design of Studies

"We typically expect results from two adequate and well-controlled clinical trials to provide substantial evidence of efficacy, particularly for a novel indication in which there are sufficient numbers of patients," the FDA said in a briefing document.

"[GlaxoSmithKline] conducted neither a proof-of-concept study nor a formal dose-ranging study in COPD patients prior to conducting the phase 3 program with mepolizumab; rather, the dose selection (100 mg every 4 weeks [Q4 weeks]) relied on information garnered from the severe asthma development program," it said.

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