Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review

Abstract

Current pharmacological treatments for chronic obstructive pulmonary disease (COPD) are mostly limited to inhaled bronchodilators and corticosteroids. Azithromycin can contribute to exacerbation prevention. Roflumilast, a phosphodiesterase (PDE) 4 inhibitor administered orally, also prevents exacerbations in selected patients with chronic bronchitis, recurrent exacerbations, severe airflow limitation and concomitant therapy with long-acting inhaled bronchodilators. This outcome likely results from anti-inflammatory effects since PDE4 is expressed by all inflammatory cell types involved in COPD. The use of this agent is, however, limited by side-effects, particularly nausea and diarrhea. To address remaining unmet needs and enrich therapeutic options for patients with COPD, inhaled dual PDE3/4 inhibitors have been developed, with the aim of enhancing bronchodilation through PDE3 inhibition and modulating inflammation and mucus production though PDE4 inhibition, thus producing a potentially synergistic effect on airway calibre. Experimental preclinical data confirmed these effects in vitro and in animal models. At present, RPL554/ensifentrine is the only agent of this family in clinical development. It decreases sputum markers of both neutrophilic and eosinophilic inflammation in patients with COPD. Clinical Phase II trials confirmed its bronchodilator effect and demonstrated clinically meaningful symptom relief and quality of life improvements in these patients. The safety profile appears satisfactory, with less effects on heart rate and blood pressure than salbutamol and no other side effect. Altogether, these data suggest that ensifentrine could have a role in COPD management, especially in addition to inhaled long-acting bronchodilators with or without corticosteroids since experimental studies suggest potentiation of ensifentrine effects by these agents. However, results from ongoing and future Phase III studies are needed to confirm both beneficial effects and favourable safety profile on a larger scale and assess other outcomes including exacerbations, lung function decline, comorbidities and mortality.

Pathological Mechanism and Targeted Drugs of COPD

“…81 PED3 is widely distributed in T lymphocytes, and lymphocyte function can be regulated by inhibition of PED3; inhibiting PED4 can reduce IL-4 and 5 gene expression in TH2 cells, decreases levels of inflammatory factors and has a synergistic effect with PED3 inhibitors in T cells. 82 Clinical evidence 83,84 also indicated that PED3/4 inhibitors (RPL-5 and roflumilast) both improve the lung function in COPD patients. However, when these patients simultaneously use standard bronchodilators, the function of RPL-554 and roflumilast benefits little.…”

Perspectives on Ensifentrine and Its Therapeutic Potential in the Treatment of COPD: Evidence to Date

“…In 4-week, phase II clinical trials, nebulized drug given twice a day alone or in combination with other bronchodilators, showed sustained bronchodilation and improvement in FEV1, improvement in symptoms judged by questionnaires, improvement in residual volumes and COPD symptoms. 19 , 24 …”

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

“…Although phosphodiesterase 4 (PDE4) inhibitors appear to be potential agents for asthma and chronic obstructive pulmonary disease (COPD) [37], they have also begun to be investigated for CNS diseases, such as memory impairments or multiple sclerosis, among others [38]. This is the case for compound 23 (Figure 7a), whose fumarate salt was considered as a potential candidate for the treatment of Alzheimer's disease [39].…”