General Information

Daliresp (roflumilast) is a selective phosphodiesterase 4 (PDE4) inhibitor. Inhibition of PDE4 activity reduces the release of inflammation mediators and can counteract damage to tissue, allowing respiratory muscles to relax and therefore potentially improving lung function.

Daliresp is specifically indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Daliresp is supplied as a tablet for oral administration. The recommended initial dose is is one 500 microgram (mcg) tablet per day, with or without food.

Mechanism of Action

Daliresp (roflumilast) is a selective phosphodiesterase 4 (PDE4) inhibitor. Inhibition of PDE4 activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which Daliresp exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

Clinical Trial Results

The FDA approval of Daliresp was based on eight randomized double-blind, controlled, parallel group clinical trials in 9,394 adults. Of the eight trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months duration that evaluated the efficacy of Daliresp 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of Daliresp on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of Daliresp (250 mcg and 500 mcg once daily) as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. COPD exacerbations and lung function (FEV1) were co-primary efficacy outcome measures in the four 1-year trials. Lung function (FEV1) alone was the primary efficacy outcome measure In the two 6-month supportive efficacy trials.
Effect on Exacerbations
Trials 3 and 4 failed to demonstrate a significant reduction in the rate of COPD exacerbations. Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed. In both trials, Daliresp 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo.
Effect on Lung Function
In Trials 3, 4, 5 and 6 Daliresp 500 mcg once daily demonstrated a statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials.