The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease

ABSTRACT

Introduction: Cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE)4 is an intracellular target that can be exploited to the treat chronic obstructive pulmonary disease (COPD), given that it is expressed in all inflammatory cells implicated in this inflammatory airways disease. At the present time, roflumilast is the only PDE4 inhibitor that has received regulatory approval for use in patients with COPD.

Areas covered: The preclinical, clinical and post-marketing development of roflumilast is described. Furthermore, a critical analysis of the clinical data and positioning of this drug is undertaken in this review

Expert opinion: The identification of a subset of COPD patients, namely those suffering from severe airflow obstruction with symptoms of chronic cough and sputum and a history of previous exacerbations, as a specific target for roflumilast with the goal of reducing exacerbations, was entirely casual because the delineation of a ‘chronic bronchitis’ responder group was clearly a post-hoc finding. However, it was useful to design prospective clinical trials that demonstrated reduced exacerbations in this specific subset of patients towards whom roflumilast therapy is now targeted. In any case, these pivotal trials still do not provide more accurate identification of the type of exacerbation to be treated by roflumilast. The identification of the right biological COPD exacerbation phenotype and/or the right clinical COPD phenotype are the only means that could justify the use of roflumilast as a first line anti-inflammatory therapeutic approach.

KEYWORDS:

• Clinical trials
• COPD
• PDE4
• phenotype
• roflumilast

Article highlights

• PDE4 is the predominant PDE expressed in the majority of inflammatory cells implicated in inflammatory airways disease such as eosinophils, neutrophils, T cells and macrophages, airway epithelial cells and endothelial cells, and therefore its inhibition may also have inhibitory effects upon both inflammatory and immune cells.

• Roflumilast is a potent PDE4 inhibitor. In vitro and in vivo animal experiments have shown that it is very effective in inhibiting mast cells, eosinophils, neutrophils, T lymphocytes, and macrophages that play a central role in COPD.

• In the light of the results of pivotal trials, roflumilast has been approved by the most important regulatory authorities to treat severe COPD in patients with chronic bronchitis and a history of frequent exacerbations, although its relatively poor tolerability.

• Post-marketing investigative activity has documented that roflumilast prevented moderate and severe exacerbations and improved lung function in patients with severe COPD and chronic bronchitis who continued to have exacerbations despite full inhaled combination therapy (LABA+LAMA+ICS).

• Since it seems possible preventing COPD exacerbations according to their biologic nature, it is important to better identify the type of biologic COPD exacerbation that can be treated by roflumilast.

• The identification of the right type of biologic COPD exacerbation and/or the right clinical COPD phenotype is the only means that could justify the use of roflumilast as a first anti-inflammatory therapeutic approach because in this case benefits would largely exceed harms.

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Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.