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Amanda Gardner
September 13, 2011

rx-bottle-dalirespGetty ImagesPeople with chronic obstructive pulmonary disease (COPD)—a lung condition thats one of the biggest killers in the nation—now have a new treatment option: a once-a-day pill called Daliresp (roflumilast).

The U.S. Food and Drug Administration (FDA) approved the drug in March 2011. But the process was not smooth sailing. In 2010, an FDA advisory panel recommended against approving the drug. Even though the FDA almost always follows the advice of such expert panels, the agency went ahead and gave Daliresp a thumbs up anyway.

So should COPD patients be worried about taking the drug? No, says FDA spokesperson Morgan Liscinsky. According to Liscinsky, even though the FDA panel recommended against the drugs approval, "the final 10-to-5 vote by the advisory committee does not fully describe how the committee members viewed the evidence to support the safety and efficacy of roflumilast."

On separate questions, the panel had actually voted 9-to-6 in favor of adequate demonstration of efficacy (meaning that the studies suggested that the drug actually worked) and, again, 9-to-6 in favor of adequate demonstration of safety, says Liscinsky. "There was considerable positive opinion regarding its safety or efficacy."

But the committee had been asked to vote on a broader indication for the "maintenance treatment of COPD," which Liscinsky says the data did not support, rather than a more narrow use for treating the symptoms of exacerbations. Exacerbations are periods when COPD symptoms, such as shortness of breath and coughing, can get much worse due to an infection or other problem, and patients can wind up in the hospital.

Another major issue that held the panel back from giving the drug its blessing was that the group had to vote on whether it should be approved for a larger group of COPD patients. “People with mild disease could have been included in the [advisory committees] vote, and thats the major difference,” says Stephen Rennard, MD, a professor of medicine at the University of Nebraska Medical Center, in Omaha. Dr. Rennard is also a consultant to Forest Laboratories and Nycomed, the U.S. and European/Canadian companies, respectively, that own the license for roflumilast.

When the FDA finally approved Daliresp, it was to treat bronchitis-related symptoms, such as cough and excess mucous in people with severe or very severe COPD who have a history of exacerbations.

Daliresp is not approved for people who have COPD involving emphysema or for patients younger than 18. (The study was conducted in patients 40 and older.)

Next Page: Side effects of Daliresp [ pagebreak ]Dr. Rennard, who was a presenter at the FDA advisory committee in 2010, thinks that "if the committee had voted on the narrower indication, it probably would have gone through,” meaning the advisory committee would have said yes to the drugs approval for patients with at least severe COPD. He adds that it was in the severe and very severe COPD groups that Daliresp trials found the drug to have the clearest benefit.

Of the 12 million people in the U.S. who are estimated to have COPD, Dr. Rennard says that approximately 3 million have severe COPD and chronic bronchitis and could benefit from Daliresp.

Side effects of Daliresp
The main trial on Daliresp, funded by Nycomed, was published in 2009 in the Lancet. It found that the drug improved lung function and resulted in a 17% reduction in the number of exacerbations.

On the other hand, 14% of patients in the trial stopped taking the drug as a result of side effects, versus 12% in the control group. The most common side effects were gastrointestinal problems such as nausea and diarrhea, some loss of appetite and weight loss, and back pain and headaches.

In addition, there may be a risk of psychiatric problems, including insomnia, anxiety, and depression. Among the nearly 12,000 patients who participated in Daliresp trials, there have been three suicides and two suicide attempts in the group receiving Daliresp compared with no suicides or suicide attempts in the placebo group. The patient medication guide that will be packaged with Daliresp states that doctors should weigh the risks and benefits before prescribing the drug to patients with a history of depression or suicidal behavior.

And there may be a higher cancer incidence among people taking Daliresp. Of study subjects who developed tumors, 60% were in the Daliresp group and 40% in the placebo group. However panelists were reportedly skeptical that Daliresp actually increases the risk of cancer since the tumors were most likely present before the study began.

Next Page: Why new COPD drugs are important [ pagebreak ] Roflumilast, which has recently become available in Europe under the brand name Daxas, is the first in a new class of drugs for COPD, which inhibit an enzyme called phosphodiesterase type 4.

One hope is that phosphodiesterase type 4 inhibitors may actually slow the progression of the disease, says Carl Boethel, MD, assistant professor of internal medicine at Texas A&M Health Science Center College of Medicine and at Scott & White Healthcare, in Temple. Although this is also the hope for current therapies, Dr. Boethel says that so far none of them have actually been found to halt disease progression.

"By the time a patient with COPD begins to experience shortness of breath, theyve usually done significant damage to their lungs," says Dr. Boethel. "We hope that [roflumilast] would also help with severe lung disease."

Although doctors look forward to the possibility of new treatments for COPD, there are other options, says Len Horovitz, MD, an internist and pulmonary specialist with Lenox Hill Hospital, in New York City.

These include bronchodilators, which are drugs that open up the airways and make it easier to breathe. Unlike roflumilast, these drugs are prescribed for both bronchitis and emphysema symptoms related to COPD.

Bronchodilators come in several varieties. One of the most common, albuterol, is a beta2-agonist that is short-acting and used as a "quick fix" for shortness of breath. People who have all stages of COPD severity keep a short-acting inhaler on hand in case of emergencies, Dr. Horovitz says. Albuterol is sold in inhalers or as a liquid that can be used in a nebulizer, a machine that creates a fine mist that is inhaled. Examples of brand names are Proventil, Ventolin, and Volmax.

There are also long-acting beta2-agonists such as salmeterol (Serevent) and Advair, which is a combination of salmeterol and a corticosteroid called fluticasone. (Corticosteroids are anti-inflammatories that come in inhaled and oral versions.)

Next Page: Daliresp may be combined with other drugs [ pagebreak ] Many products use a combination of one or more COPD drugs; in addition to Advair, examples include brand name drugs like Combivent and Symbicort.

Two trials published in the Lancet in 2009 looked at the effect of Daliresp in patients who were already taking salmeterol or tiotropium, and found that Daliresp improved lung function more than either bronchodilator alone. The authors suggest that Daliresp gives added benefit because it has an anti-inflammatory effect while the bronchodilators open up the airways.

One advantage of Daliresp is that it comes in pill form, which should make it more attractive to patients.

Dr. Boethel says he was heartened by the FDAs approval of Daliresp.

"Pulmonologists always get a little excited when something new comes out that may give our patients some relief," says Dr. Boethel. "But this still remains a pretty bad disease. COPD is one of the few diseases that the mortality has increased since the '60s. We used to think of COPD as a disease of elderly men, primarily veterans, and now its more a disease of people under 65 and it affects women more than men."

But as with all drugs, "Daliresp should be used cautiously and the potential benefits need to be considered against the potential risks," Dr. Rennard says.

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