SILVER SPRING, MD. – Olodaterol, an inhaled long-acting beta2-adrenergic agonist, is an effective bronchodilator and should be approved for the treatment of chronic obstructive pulmonary disease, based on clinical trials in more than 3,000 patients with moderate to very severe COPD, the majority of a Food and Drug Administration advisory panel agreed at a meeting on Jan. 29.
The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 15-1, with one abstention, to recommend approval of olodaterol for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema – the indication proposed by the manufacturer, Boehringer Ingelheim. Olodaterol is formulated in an inhalation spray solution, administered once a day via a metered dose inhaler (the Respimat device), at a dose of 5 mcg (two actuations of 2.5 mcg each).
The panelists voting in favor of approval agreed that clinical trial results showed that the drug had a bronchodilator effect comparable to other established bronchodilators, in a real-world setting where patients were on background medications, and at a dosing regimen that was similar to other treatments.
In separate votes on safety and efficacy, the panel also voted 15-1, with 1 abstention, that the data provided "substantial evidence" that the drug was effective; and 15-1, with 1 abstention, that the safety profile was adequate for the proposed indication and was comparable to that of other LABAs. But the panel recommended postmarketing surveillance of safety, including malignancies, and safety in black patients, who made up less than 5% of the enrolled patients in the studies.
In the studies, there were more neoplasms among those treated with olodaterol, but the increase was not statistically significant and did not reach the level of a safety signal, according to the company. But several panelists said that they were struck by the four diagnoses of small-cell lung cancers in patients on the 10-mcg daily dose that was also tested in the studies. While this was not a reason to recommend against approval, they said that malignancies – lung cancers in particular – in treated patients should be closely monitored after approval.
In four pivotal studies presented by the company, treatment with olodaterol (5 mcg or 10 mcg a day) was compared with placebo in 3,104 patients with moderate to very severe COPD (mean age 65 years) who were also on background medications (a muscarinic antagonist in 47%, an anti-inflammatory in 52%, a muscarinic antagonist and an antinflammatory in 29%, and a muscarinic antagonist with an inhaled corticosteroid and a xanthine in 5%).
Compared with placebo, treatment with 5 mcg per day was associated with statistically significant improvements in the two primary endpoints – FEV1 AUC (0-3 hours) and trough FEV1 responses – at 12 weeks in the two studies conducted primarily in the United States, and at 24 weeks in the two studies conducted primarily in Europe. Improvements in lung function with the 5-mcg dose were comparable to the 10-mcg dose, which is not a proposed dose.
Death rates and serious adverse events were similar in patients treated with olodaterol and comparators, and COPD exacerbations were the most common cause of death.
Boehringer Ingelheim has also proposed that the labeling include a claim that treatment with olodaterol increased exercise tolerance, increased respiratory capacity, and reduced lung hyperinflation. If approved by the FDA, this would be the first exercise tolerance claim to be included in labeling of a COPD drug, but based on the comments of the panel, this is unlikely.
In the study, the benefits in exercise tolerance after 6 weeks of treatment were based on effects on exercise tolerance testing performed 2 hours after the morning dose, at the time of the drug’s peak effect, in about 308 patients. It was unclear whether the effects could be maintained if the test had been performed later, which is particularly important because the indication is for maintenance treatment, according to the FDA reviewers.
The panel was not asked to vote on the exercise claim but discussed whether the results were clinically meaningful. Several panelists said that the improvements in exercise tolerance were notable, but since improvements were measured in a laboratory setting 2 hours after patients received the daily dose of olodaterol, it would be useful to evaluate how these improvements affected an individual’s activities of daily living. It would also be useful to provide a measurement later in the day to see if the effects persist throughout a period of time the patient may be active.
If approved, olodaterol will be marketed as Striverdi Respimat. It has already been approved in more than 60 countries.