Once-Daily Drug on Horizon for COPD
BY ELIZABETH MECHCATIE
Elsevier Global Medical News
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease, to be taken at a dose of 75 mcg once daily.
Two weeks later, however, the FDA told the drug’s maker, Novartis, that the agency would need 3 more months to complete the review of indacaterol’s research data.
At an initial meeting in March, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
The majority of the panel agreed that the 150-mcg once-daily dose had not been shown to be effective, largely because of the limited amount of data directly comparing the two doses.
Indacaterol, a long-acting beta2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as panel chair Dr. Peter Terry, FCCP, professor of medicine, Johns Hopkins University, Baltimore, said, “no compelling evidence that there was a significant difference” between the two doses.
The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.
Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose, and also because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol. In studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol, which raised concerns because treatment with inhaled LABAs as monotherapy has been associated with severe asthma exacerbations and asthma-related deaths, described in the boxed warning included in the prescribing information of these drugs. Although the mechanism has not been identified, data from controlled and epidemiologic studies suggest that higher doses may contribute to this increased risk, according to the FDA.
In response, the company conducted more studies and analyses, and submitted data on the 75-mcg and 150-mcg once-daily doses in about 2,700 patients with COPD, and proposed those two doses for approval, recommending the 150-mcg dose as the starting dose.
At the FDA meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 mostly white patients with COPD, whose mean age was about 64 years. After 12 weeks, there were significant improvements in lung function, as measured by trough FEV1 associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.
FDA reviewers concluded that there was no clinically meaningful difference in efficacy between the 75-mcg dose and the two higher doses, raising the question of whether the higher dose was necessary. Most of the panelists agreed.
“I do believe that at this dose a substantial number of patients with moderate to severe COPD in the United States will benefit from this medication, without substantial risks,” said one of the panelists, Daren Knoell, Pharm.D., professor of pharmacy and medicine at Ohio State University and the Davis Heart and Lung Institute, Columbus. He referred to “consistent” evidence across virtually all trials that the 75-mcg once-daily dose benefited most patients.
Novartis has proposed a risk evaluation and mitigation strategy (REMS) to manage the potential risks of the drug, which would include educating health care professionals about the appropriate indications for indacaterol and about the increased risk of asthma-related deaths associated in asthma patients treated with LABAs as monotherapy.
If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; currently, only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment.
A final decision on approval is not expected until the summer. In a statement issued in late March, Novartis said that the FDA has asked for a 3-month extension of its review of indacaterol, which is expected to be completed by July.
If approved, the company plans to market indacaterol in the United States as the Arcapta Neohaler.
Novartis has conducted studies of the drug in patients with asthma, but is not filing for approval for an asthma indication in the United States or elsewhere. Some concern about off-label use of the product in patients with asthma was expressed at the meeting.
The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict, but this was not necessary at this meeting.
COMMENTARY
Dr. Darcy Marciniuk, FCCP, comments: The desire to have an effective once-a-day longacting beta2 agonist in our COPD tool kit may soon become a reality. The medication dosing needs to get sorted out – we’ll be watching closely for the FDA opinion on this issue. The real benefit of this medication may be in future single-delivery system combinations with other effective inhaled COPD therapies.
