Regulatory Decision Summary for Spiriva Respimat

Spiriva Respimat showed a statistically significant improvement in lung function [Forced Expiratory Volume in the first second (FEV1) peak0-3h] and trough FEV1, co-primary endpoints, on top of maintenance treatment with high dose inhaled corticosteroids (ICS) and long-acting beta agonists (LABA) in patients with severe persistent asthma in two confirmatory Phase III 48-week pivotal clinical studies. In addition, Spiriva Respimat showed a sustained bronchodilation effect over 24 hours that was maintained during the 24-week treatment period. In the pooled analysis, treatment with Spiriva Respimat delayed the time to first severe exacerbation compared with placebo resulting in a risk reduction of 21% for a severe exacerbation, the third co-primary endpoint. Spiriva Respimat provides sustained bronchodilation, which was associated with an improvement in lung function and reduction in severe exacerbations, however, symptomatic improvements were not consistent for the two studies.

One uncertainty regarding the efficacy of Spiriva Respimat is that the minimal clinically important improvement of lung function on top of high-dose ICS + LABA has not been defined nor has the minimal clinically important difference for the reduction of exacerbations. Improvement in lung function and reduction in severe exacerbations, however, were demonstrated even though patients were already taking high-dose ICS + LABA.

The systemic exposure of tiotropium in asthma patients was lower than in patients with chronic obstructive pulmonary disease (COPD) and was dose dependent. The most frequently reported adverse events were in the system organ class of respiratory, thoracic and mediastinal disorders, and the percentage of patients experiencing adverse events was generally comparable between treatment with tiotropium and placebo. The common adverse event profile for Spiriva Respimat in the treatment of asthma is similar to that for the treatment of COPD and may be attributed to the anticholinergic properties of tiotropium bromide. The most common drug-related adverse events were dry mouth, dry throat and dysphonia which were more common with treatment with tiotropium. Both ß2-adrenergic agonists and muscarinic antagonists can affect the cardiovascular system, but the safety database in asthma is limited. Some evidence regarding the safety may be obtained from the COPD population.

Currently in Canada, there are no long-acting muscarinic antagonists for the treatment of asthma, but several are indicated for the treatment of COPD. The recommended indication for Spiriva Respimat is limited to the patient population of the pivotal clinical trials, and is indicated only as add-on treatment to high dose ICS + LABA in patients with severe persistent asthma who remain symptomatic and who had experienced a severe asthma exacerbation in the previous year. Tiotropium appears to be well tolerated in this study population as an add-on treatment to maintenance asthma therapy.

Based on the recommended indication and dosage administration, and the evidence supporting the safety and efficacy of Spiriva Respimat provided in the submission, Spiriva Respimat is considered to have a favourable risk-benefit profile.