At the American Thoracic Society (ATS) conference in Washington DC in May 2017, the importance of the phosphodiesterase 4 (PDE4) pathway in chronic obstructive pulmonary disease (COPD) was confirmed to reduce the risk of exacerbation, improve symptoms of cough and sputum, and reduce eosinophil cell count in bronchial biopsies and induced sputum.

The PDE4 pathway was previously shown to be an effective agent in reducing the risk of exacerbations in patients with severe chronic obstructive pulmonary disorder (COPD) associated with chronic bronchitis and an exacerbation history. AstraZeneca’a Daliresp (roflumilast) was the first-to-market, and remains the only oral PDE4 inhibitor (PDE4i) available in the COPD market in the US and EU.

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Daliresp’s uptake has been hindered due to reimbursement and dispensing obstacles in the US and regulatory pressures in the EU. Additional clinical benefits such as improved symptoms of cough and sputum production, presents an opportunity for AstraZenca to overcome an underwhelming initial performance.

Phase IV, double blind study RE2SPOND evaluated the efficacy of Daliresp on cough and sputum production measured by the EXAcerbation of Chronic Pulmonary Tool-Patient Reported Outcomes (EXACT-PRO) questionnaire. Patients with severe to very severe COPD with chronic bronchitis and at least two exacerbations in the previous year were randomised to receive Daliresp (500mcg, n=1,178) or placebo (n=1,174) both once daily in addition to background therapy, including inhaled corticosteroids / long-acting beta2-agonists (ICS/LABA) with or without long-acting muscarinic antagonists (LAMA) therapy, for 52 weeks. In addition to change in EXACT-PRO, change in breathlessness, cough and sputum, and chest symptom subdomains were measured over the treatment period. Participants were required to electronically record their COPD symptoms every night.

At Week 52, a significant difference between the Daliresp and placebo group in mean change from baseline in the EXACT-PRO total score was not demonstrated. Analysis of EXACT-PRO subdomains demonstrated that Daliresp significantly improved cough and sputum domain scores at all time points (Week 4, 12, 20, 28, 40, and 52) compared with placebo (p<0.0001 for all time points). Treatment with Daliresp was also associated with significant improvements in breathlessness domain scores at Week 4 and Week 28 (p≤0.0286), but significant differences in chest symptoms domain scores were not observed between the Daliresp and placebo group.

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In addition, the ROflumilast Biopsy European Research Trial (ROBERT), a double-blind, randomised, parallel-group, placebo controlled trial, demonstrated that Daliresp significantly reduces eosinophil cell count in bronchial biopsies and induced sputum. Moderate to severe COPD patients (n=158) were randomised to receive Daliresp (500mcg) or placebo for 16 weeks in addition to bronchodilator therapy without ICS therapy. The primary endpoint, change in the number of cluster of differentiation 8 positive (CD8+) inflammatory cells in bronchial biopsy tissue from baseline to Week 16, was not met. However, Daliresp was associated with a 47% reduction in the number of eosinophils in bronchial tissue samples compared with placebo (p=0.0046). In addition, Daliresp demonstrated a significant reduction in both absolute and differential eosinophil cell counts in induced sputum (p=0.0042 and p=0.0086, respectively). Therefore, the efficacy of Daliresp may be mediated by effects on lung eosinophils, a potential biomarker for ICS treatment in COPD.

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Focusing on the competition within the PDEi class, Verona Pharma’s RPL554, a dual inhibitor of the PDE3 and PDE4 enzymes, and Chiesi’s CHF-6001, a PDE4 inhibitor, are both in Phase II development for COPD. Although RPL554 may offer an advantage in the COPD market space targeting both PDE4 and PDE3, with the potential to minimize gastrointestinal side effects associated with PDE4 inhibitors, Phase III trials with RPL554 have yet to be conducted, leaving Daliresp with market exclusivity for the foreseeable future. GlobalData expects Daliresp to garner $137 million in sales across the six major pharmaceutical markets (US, France, Germany, Italy, Spain, and UK) in 2025.