FDA Panel Votes Against Roflumilast for COPD

Emma Hitt, PhD

April 09, 2010

April 9, 2010 — The US Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee voted 10 to 5 on April 7 against use of roflumilast (Daxas, Forest Laboratories), a once-daily phosphodiesterase 4 inhibitor being evaluated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in patients with chronic bronchitis who are at risk for chronic exacerbations.

Earlier in the session, the FDA committee, which consists of outside medical experts that advise the agency, voted 9 to 6 that roflumilast was both effective and safe as maintenance treatment for COPD. However, later during the meeting, the committee voted that safety and efficacy data did not appear to be strong enough to warrant approval of the drug; the overall opinion was that roflumilast had too many adverse effects to offset what the FDA referred to as a "modest" increase in lung function.

The panel was also unable to determine the relative efficacy of roflumilast compared with other available COPD treatments, as none of the 18 late-phase clinical trials directly compared roflumilast with other agents.

Roflumilast would be a first-in-class phosphodiesterase 4 inhibitor intended for the treatment of COPD. In pivotal studies reviewed at the committee meeting, roflumilast resulted in a significant increase in prebronchodilator forced expiratory volume in 1 second, increasing this measure by nearly 50 mL after treatment compared with baseline (P < .0001). However, data also indicated that 14% of patients discontinued the drug because of diarrhea, nausea, weight loss, and psychiatric adverse events including suicide (3 suicides and 2 suicide attempts in patients receiving roflumilast compared with none receiving placebo).

Cancer incidence was also higher with roflumilast: out of 218 cancer/tumor events, 60% occurred in patients in the roflumilast group compared with only 40% in the placebo group.

Lawrence Olanoff, MD, PhD, president and chief operating officer of Forest, stated during the meeting that the voting outcome was a "bit of a disappointment," but added that "at the end of the day, we didn't hear anything that couldn't be negotiated."

The Swiss company Nycomed submitted the drug's application to the FDA in July 2009; the application was taken over by Forest in December. According to the FDA, Forest has amended the application and has asked for a more restrictive indication for use and a warning regarding the risk for neuropsychiatric adverse effects.

The FDA is expected to make a final decision about roflumilast in May.

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