PDE4D: A target for the treatment of airway hyper-responsiveness in asthma

The incidence of asthma has dramatically increased over recent years. Furthermore, although currently available treatments are generally effective patient compliance is poor, especially with respect to inhaled treatment. In addition 5% of patients are unresponsive to these treatments and it is this cohort that accounts for a large segment of asthma related healthcare costs. Novel non-inhaled treatments such as the recently approved Xolair therefore stand to offer considerable benefit to asthmatics.

Global revenue for 2001 from asthma therapies has been reported by some to be as high as $11.7 billion. The interest generated by new and emerging asthma therapeutics, the increased need for these treatments, the commercial benefit that they could enjoy and the competition that they will experience, recently prompted LeadDiscovery to produce a state of the art of asthma therapeutics (Click here). One of the key targets that was evaluated was PDE4.

Like asthma, there is a pressing need to develop new treatments for COPD. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year. A global market of US$2.8 billion parallels this serious healthcare problem. There is a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD as no currently available drug therapy reduces the relentless progression of COPD. In common with asthma, PDE4 inhibitors are being developed for the treatment of COPD.

Cilomilast and Roflumilast are the most advanced PDE4 inhibitors and in September 2003, two major announcements were made regarding these compounds which stand to shape future development of the field. In an initial announcement, the FDA advisory panel recommended rejection of GSK's Cilomilast due to fears of side effects. This was followed however by an announcement by Altana that their better tolerated Roflumilast demonstrated efficacy in a phase III study of COPD patients. The regulatory activity surrounding PDE4 inhibitors as well as key finding relating to the development of PDE4 inhibitors are described in LeadDiscovery’s upcoming report “Phosphodiesterase 4 (PDE4) & Phosphodiesterase 5 (PDE5): Pharmaceutical advances and the identification of stroke & pulmonary hypertension as new therapeutic targets”. One of the key issues addressed in this report relates to the nausea and emesis that disadvantaged many early inhibitors and strategies developed to avoid these problems. Approaches including the development of molecules that do not penetrate the blood brain barrier and the identification of those that are selective for PDE4A and PDE4B over PDE4D isoforms, the latter having been suggested to be responsible for nausea.

In 2000, Hansen et al reported that mice that do not express PDE4D enzymes are resistant to cholinergic airway contraction both under control conditions and in a model of asthma. This study suggested that to maximize the therapeutic efficacy of PDE4 inhibitors, drug development strategies should lean towards the advancement of molecules that inhibit PDE4D (as well as other isoforms) without causing nausea. More recently the same group have investigated the pharmacology of this phenomenon in vitro. In agreement with their in vivo findings tracheal smooth muscle of PDE4D knock out mice displayed a considerably reduced response to muscarinic cholinergic stimulation as compared to controls. This was not due to a generalized loss of contractility as the responses to KCl or arginine vasdopressin were unaffected.

In control mice approximately 50% of total PDE activity in tracheal tissue from control mice was inhibited by the PDE4 inhibitor rolipram. In knock out mice basal activity was reduced by 50% and was unaffected by rolipram, findings reflected in increased basal and stimulated cAMP levels. Consistent with these findings PGE2, which stimulates cAMP levels was able to relax carbachol-precontracted tracheas more potently in tissue from mutant animals than from controls. A similar increase in sensitivity to endogenous prostaglandins was shown to be responsible for reduced cholinergic responsiveness in vivo.

This study therefore confirms that deleting PDE4D activity limits the response to cholinergic stimulation of airway contractility and that this is due to enhanced levels of cAMP accumulating in response to endogenous prostanoids. The therapeutic potential of PDE4D inhibitors is thus confirmed at least in the context of airway hyper-responsiveness, a phenomenon that is particularly important in asthma. Thus PDE4 inhibitors developed for the treatment of asthma should be able to block PDE4D activity in order to optimize efficacy and hence limiting CNS penetration or identifying PDE4D inhibitors that do not provoke emesis remain a pharmaceutical target. In contrast the priority for the treatment of COPD is to reduce inflammation rather than airway hyper-responsiveness. Hence the profile of PDE4 inhibitors developed for COPD may differ from that of asthma.

Entry date Wednesday, November 12, 2003

Adapted from Mehats et al, FASEB J. 2003 Oct;17(13):1831-41.