Roflumilast Approved in Europe for Chronic Obstructive Pulmonary Disease

Yael Waknine

July 21, 2010

July 21, 2010 — The European Commission (EC) has approved roflumilast once-daily tablets (Daxas; Nycomed, Inc) as an add-on to bronchodilator therapy for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis in adults with a history of frequent exacerbations.

Roflumilast is a phosphodiesterase-4 inhibitor and represents a new molecular entity — the first new drug class to be approved for patients with COPD in more than 10 years.

"Daxas...has a unique mode of action which targets the underlying inflammation in COPD and is an important addition to the current options available to doctors and patients," stated Klaus F. Rabe, MD, from the University Medical Centre Leiden, the Netherlands, in a company news release.

As the first oral anti-inflammatory to be approved for COPD, roflumilast may fill a therapeutic gap for patients with frequent exacerbations.

"There are still huge unmet needs when it comes to the medical care of patients with COPD, both in terms of just symptomatic relief — in terms of bronchodilation — but also particularly in terms of exacerbation prevention," said Andrew F. Shorr, MD, MPH, FCCP, in an interview with Medscape Medical News, noting that exacerbations are associated with substantial morbidity and mortality and lead to an accelerated decline of patient functioning.

Dr. Shorr is associate chief of the Department of Pulmonary & Critical Care Medicine at Washington Hospital Center and associate professor of medicine in the Department of Pulmonary & Critical Care Medicine at Georgetown University, Washington, DC.

Clinical Study Findings

The European approval was based primarily on data from 2 pivotal, 1-year phase 3 trials of more than 3000 patients with COPD, showing that roflumilast significantly improved moderate to severe exacerbations and prebronchodilator forced expiratory volume in 1 second relative to placebo — an effect that was independent of concomitant long-acting β2-agonist therapy.

Two supportive 6-month studies demonstrated that roflumilast significantly improved lung function relative to placebo when added to tiotropium or salmeterol — 2 commonly used bronchodilators.

"What's interesting about the data — in terms of the whole series of articles published in the Lancet — is that there clearly was an additive effect to other standard therapies used in COPD, suggesting that Daxas really would have some efficacy in exacerbation prevention," said Dr. Shorr.

"The main additional benefit of Daxas on top of what is already achieved with bronchodilators is to reduce the number of exacerbations, or flare-ups, which are the events that really concern the patients who experience them. For patients with COPD associated with chronic bronchitis and a history of flare-ups, Daxas can make a real contribution," said Neil Barnes, MD, in a company news release.

Dr. Barnes is a professor of respiratory medicine at Barts and the London Hospital in the United Kingdom.

US Approval Blocked Because of Safety Concerns

In an April 7, 2010, meeting, the US Food and Drug Administration's Pulmonary-Allergy Drugs Advisory Committee voted 10 to 5 against recommending approval of roflumilast.

According to Dr. Shorr, the negative decision was primarily related to safety concerns.

"[The advisory committee members] were focused mainly on safety in terms of psychiatric issues — there were concerns about suicide related to the molecule — and also gastrointestinal tolerability. There was a lot of gastrointestinal distress reported with this drug in clinical trials."

Commenting on the possibility of FDA approval in the near future, Dr. Shorr was skeptical.

"My suspicion is that with the current data package, I don't think [roflumilast] will be approved in the US in the next year or so.... I think right now the FDA is very, very focused on issues related to safety, and the people at Forest and Nycomed have a very high burden to overcome," Dr. Shorr said. "You have a lot of very smart people on that advisory committee for the FDA, and it wasn't even a close vote. [The European approval] demonstrates that even with very similar data, it's possible to interpret it in different ways and to evaluate risks and benefits in different ways as well."

If approved in the United States, roflumilast will be marketed by Forest Laboratories, Inc, under license from Nycomed.


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