FDA Panel Backs New COPD Combination Medication

Damian McNamara

September 10, 2013

In an 11-to-2 vote, members of the US Food and Drug Administration (FDA) Pulmonary Allergy Drugs Advisory Committee today supported approval of a new combination medication for long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Umeclidinium and vilanterol powder for inhalation (Anoro Ellipta, GlaxoSmithKline) got the nod after the committee considered preclinical efficacy and safety data. In a unanimous 13-to-0 vote, members also agreed that efficacy data demonstrated a clinically meaningful benefit for patients with moderate-to-severe COPD, including chronic bronchitis and emphysema.

More debate and less certainty surrounded the medication's safety profile. Although the panel voted 10 to 3 that safety of umeclidinium and vilanterol 62.5/25 mcg was demonstrated for the proposed indication, many panel members voiced concerns. A relatively low incidence of adverse cardiovascular events reported in primary efficacy and long-term safety studies, for example, left some wondering if the preclinical data somehow missed any important safety signals. Some called for labeling if approved to carry a warning about potential, unknown risks for patients with cardiovascular disease. The agency is already considering wording that the agent should be used with caution in patients with cardiovascular disorders, according to an FDA employee at the meeting.

Most panel members called for further study regardless of how they voted on the safety question. Should the medication gain marketing approval from the FDA, they suggested postmarketing surveillance to detect any significant adverse events, particularly as it enters more into the clinical setting outside the confines of well-controlled clinical trials.

"There seems to be very high level of agreement among the committee members regarding a need for postmarketing studies," said David B. Jacoby, MD, chairperson of the committee and professor of medicine at Oregon Health & Science University, in Portland. Dr. Jacoby voted to recommend approval of the medication.

Also voting yes was John Hoidal, MD professor and chair of medicine at the University of Utah, in Salt Lake City. The evidence "provides efficacy of a magnitude likely to be beneficial to COPD subjects and issues regarding safety were well discussed here. Clearly, follow-up postmarketing [studies] looking at safety are very important."

Nizar N. Jarjour, MD professor and head of allergy, pulmonology and critical care medicine at the University of Wisconsin School of Medicine and Public Health, in Madison, said he voted yes because there is a real need for additional treatments for COPD.

Judith Voynow, MD, professor of pediatrics at Children's Hospital of Richmond, Virginia, also voted yes. She stated that data were convincing on efficacy and safety with the caveats the panel discussed.

One of the votes against FDA approval came from James K. Stoller, MD, professor of medicine at Cleveland Clinic, in Ohio, who favored delaying marketing until additional safety studies are complete. "Like my colleagues, I'm impressed with appeal of a once-daily drug with meaningful efficacy. On the other hand, I have a concern with the safety signal and concerns about generalizability [in clinical practice] that need to be addressed in the pre-marketing setting."

A few days prior to the committee meeting, some reviewers for the FDA raised concerns about some "not entirely conclusive" cardiac safety data in comments posted on the agency's Web site.

Efficacy and safety data reviewed by the committee included preclinical experience in approximately 6000 patients enrolled in phase 2 studies. This evidence included 4 primary efficacy studies with a primary outcome measure of trough FEV1 at 24 weeks; a 52-week, long-term safety study; and 2 double-blind, randomized exercise duration and lung function studies.

Neither umeclidinium, a long-acting muscarinic receptor antagonist, nor vilanterol, a long-acting selective beta-2 adrenergic agonist, are currently marketed in the US. For this reason, the FDA required GlaxoSmithKline to assess the safety and efficacy of the combination versus each component and placebo. Vilanterol was approved for treatment of COPD in May 2013 as part of a combination product with fluticasone furoate (Breo Ellipta, GlaxoSmithKline/Theravance). Although the committee reviewed preclinical data for umeclidinium and vilanterol in both 125/25 mcg and 62.5/25 mcg dosage formulations, the company only opted to pursue a new drug application for the lower dose combination.

The FDA is expected to make a conclusion by December 18, 2013.

The FDA screens Advisory Panel members for potential conflicts of interest. The agency also provides waivers for conflicts of interest for Federal employees on advisory panels and did not issue any waivers for this meeting.


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