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Selective PDE-IV inhibitors have a major role to play in the treatment of asthma and Chronic obstructive pulmonary disease

ThumbprintAsthma is a disease characterised by chronic inflammation of the respiratory tract, elicited by activation of leukocytes usually in response to environmental allergens.

Chronic obstructive pulmonary disease (COPD) is an umbrella term used to describe a number of diseases causing airway obstruction, which are the result of irritant-induced airway inflammation ñ primarily cigarette smoking. While asthma can be described as a CD4+ T-cell-driven eosinophilia, COPD is associated with increases in the number, or activity, of CD8+ T-cells, macrophages and neutrophils.

Asthma and COPD are most commonly controlled, in the long term, by the use of inhaled corticosteroids. However, unlike asthma, important components of the inflammatory cascade in COPD are not responsive to steroid treatment. Combined with the unfavourable immune system adverse events of such treatment, the need for novel, more effective antiinflammatory drugs is clear.

Cyclic adenosine monophosphate (cAMP) is a second messenger molecule that is important in many biochemical pathways, including inflammation. Increases in intracellular cAMP concentrations lead to smooth muscle relaxation, cardiac stimulation and inhibition of secretory cells.

The activity of cAMP is very tightly controlled, and the molecule can only be degraded by a family of enzymes known as cyclic nucleotide phosphodiesterases (PDE). To date, approximately 11 families of PDE isoforms have been identified and these differ significantly in terms of expression patterns and cellular compartmentalisation, meaning that each has a unique functional role.

The inhibition of PDE has long been of interest to healthcare professionals, in particular the treatment of inflammatory diseases such as asthma, COPD, arthritis and psoriasis.

What's on offer
Theophylline is an older prototypical PDE inhibitor that has been used in obstructive airway diseases for more than 60 years. However, it is dogged by a poor gastrointestinal and cardiac tolerability profile due to its non-selective inhibition of PDE in all tissues of the body. Fortunately, a cAMP-specific family of PDE (PDE-IV), expressed primarily in immune and inflammatory cells, airway smooth muscle and pulmonary nerves, has been isolated. This particular group of enzymes has been identified as playing a substantial role in leukocyte activation. In in vitro and in vivo studies, selective PDE-IV inhibitors have shown potent anti-inflammatory, aswell as bronchodilatory, activity, identifying this drug class as a potential treatment for diseases, such as asthma and COPD.

First-generation PDE-IV inhibitors proved to be potent anti-inflammatory agents, but were associated with substantial dose-limiting gastrointestinal toxicity and emesis, limiting their use. More recent second-generation PDE-IV inhibitors boast a more favourable toxicity profile. Currently, no selective PDE-IV inhibitors are available on the market, but several agents are in late-phase development.

GlaxoSmithKlineís Cilomilast is awaiting approval as a treatment of COPD in the US, and phase II and III trials are ongoing in Japan and Europe. It is an orally active compound that has demonstrated superior tolerability to the prototype PDE-IV inhibitors, despite having a similar chemical structure.

Data from two pivotal phase III European randomised double-blind trials indicated that six months of cilomilast treatment reduced the frequency of exacerbations and maintained lung function among 1,411 patients with poorly reversible COPD.

Cilomilast was associated with reductions in frequency of moderate-to-severe exacerbations compared with placebo (p < 0.05). Lung function, as reflected by forced (FEV1) expiratory volume in 1 second was maintained in patients treated with Cilomilast, but deteriorated in placebo-treated patients; this difference was statistically significant.

In a retrospective analysis, Cilomilast was also associated with lower non-drug costs and significantly greater quality-of-life benefits compared with placebo.

Roflumilast is being developed by Altana Pharma as a potential treatment of asthma and COPD. It is awaiting regulatory approval in Europe and phase III clinical trials are ongoing in the US.

Like Cilomilast, this compound is also well tolerated, and does not appear to be associated with the nausea and vomiting that have posed a problem with older PDE-IV inhibitors. In a multicentre randomised study, the tolerability profile observed in 516 patients with COPD was equivalent to that seen in placebo recipients after 26 weeks of dosing.

In a one-year study of 1,513 patients, Roflumilast recipients demonstrated significantly greater improvements in baseline FEV1 compared with placebo recipients (p < 0.001). In a study of patients with allergic asthma, Roflumilast was seen to inhibit the late asthmatic reaction and attenuate the early asthmatic reaction relative to placebo, following an allergen challenge.

Altana said that Roflumilast may also have a role in the treatment of psoriasis and allergic rhinitis.

Tetomilast is currently in phase II development with Otsuka in the US as a treatment for COPD. Preclinical studies have demonstrated the efficacy of Tetomilast in the inhibition of airway inflammation in COPD, and in a guinea-pig model of COPD induced by cigarette smoke exposure, Tetomilast resulted in improvements in specific airway resistance and neutrophilia.

Other development indications include ulcerative colitis, inflammatory bowel disorders and inflammation.

Selective PDE-IV inhibitors have an important role to play in the treatment of asthma and COPD. The introduction of one or more of these agents to the market will expand the armamentarium of treatments for these costly and burdensome diseases.

The Author
Pipeline is written by Anna Mett of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight. For more information on Adis services, contact Camille Scot-Smith on 020 7981 0733

2nd September 2008


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