Novartis AG's Arcapta Neohaler (indacaterol inhalation powder) has finally won FDA approval for chronic obstructive pulmonary disease, albeit at a single and much lower dose than the two doses originally sought and which are already available in Europe.

Arcapta was cleared at a 75 mcg once-daily dose as a long-term maintenance treatment for airflow obstruction in COPD, including chronic bronchitis and/or emphysema, the agency announced July 1. Novartis intends to launch in the first quarter of 2012.

The long-acting beta2-adrenergic agonist helps muscles around the airways of the lungs stay relaxed in order to prevent symptoms of COPD.

As expected, a boxed warning in labeling and a Medication Guide note that the LABA class increases the risk of asthma-related death and that the bronchodilator is not indicated for asthma.

The approval was hard won, following much debate about the appropriate minimum dose for good efficacy and following a "complete response" letter in October 2009. Novartis had most recently been pushing for approval of two doses: 75 mcg and 150 mcg. But safety concerns for the LABA class in patients with asthma have been high on the agency's radar. FDA's advisory committee briefing documents had indicated a preference for the 75 mcg dose and FDA's Pulmonary-Allergy Drugs Advisory Committee voted in March for the approval of the 75 mcg dose but not 150 (Also see "Arcapta Quality Of Life Data For High Dose Cannot Overcome Efficacy Questions" - Pink Sheet, 8 March, 2011.).

Lower Dose Combo Ready For Phase III

FDA's approval of only the 75 mcg dose presents a challenge for the development program for indacaterol. The drug is in Phase III at a 150 mcg dose as part of the QVA149 combination with the long-acting antimuscarinic antagonist glycopyrronium bromidel; Novartis says it has prepared a lower dose formulation of QVA149 that it is readying for Phase III.

Filing in Europe, with the higher dose, is expected in late 2012, and Societe Generale analyst Marietta Miemietz believes the U.S. filing could follow at most a year later, assuming rapid enrollment in the three-month bridging study that Novartis is expected to conduct for the U.S. formulation, she said in a July 4 note.

"This comes as a positive surprise following uncertainty with regard to the potential need for further characterization work of the lower dose QVA program, which could have entailed a multi-year delay," the analyst observed.

In its original NDA in 2008, Novartis sought approval for 150 mcg and 300 mcg doses, which were subsequently approved in Europe under the brand name Onbrez Breehzhaler ([A#1216099165884]). But FDA's "complete response" letter contends that these doses were high and questioned the data supporting the filing.

In response, Novartis lowered its requested doses to 75 mcg and 150 mcg and submitted additional data from six studies (Also see "Novartis Resubmits Onbrez To FDA; Touts Comparative Trial Against Spiriva" - Pink Sheet, 3 November, 2010.). Quality of life data showed an advantage for the higher dose. But, in the end, the FDA advisory committee was not persuaded that the 150 mcg dose had an efficacy advantage that would balance the higher risks. The panel also expressed a desire for a head-to-head study of the two doses (Also see "COPD Drug Dose Selection May Face Greater Scrutiny In Arcapta’s Wake" - Pink Sheet, 14 March, 2011.).

"Unsurprisingly, FDA's stance is in contrast with the European labeled doses of 150 mcg and 300 mcg; we note that FDA tends to exercise extreme caution with regard to respiratory agents and avoids approving more than one dose," Miemietz commented.

Nevertheless, the new U.S. label is "benign," with a boxed warning as expected and no "commercially relevant contraindications," she said.

Nod To Quality Of Life

The application was supported by six confirmatory trials in over 5,000 patients, who had a smoking history of at least a pack a day for 10 years and moderate-to-severe decreases in lung function, FDA noted in its announcement of the approval.

Labeling notes that the product's development program included three dose-ranging trials and six confirmatory trials. Dose selection was based mainly on a trial in asthma patients, even though the treatment is not approved for that condition. In the asthma study, effects of the 150 mcg and 75 mcg doses did not differ, the label reports.

In the six confirmatory trials, efficacy was measured based on changes in forced expiratory volume testing. Using this measure, all doses tested (75 mcg, 150 mcg, 300 mcg and 600 mcg) showed improvements in lung function compared to placebo after 12 weeks, the label notes.

The label also notes that pooled data from the six studies show an improvement in health-related quality of life, based on findings from the St. George's Respiratory Questionnaire in all six confirmatory studies.

-Emily Hayes (e.hayes@elsevier.com)

Novartis Finally Wins Arcapta Approval, Having Lost Battle On Desired Dose

More from Archive

More from Pink Sheet