The airway is the focus of two highly prevalent diseases, COPD (chronic obstructive bronchitis and emphysema) and asthma. Asthma affects 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action (for further details see our recent report “Asthma Therapeutics: New treatment options and emerging drug discovery targets”). COPD is also very common. Worldwide, 600 million people suffer from COPD, with some three million dying from the disease each year representing a global market of US$2.8 billion.

Although they involve different cell types, asthma and COPD are both chronic inflammatory diseases associated with cellular infiltration and activation. Neutrophil infiltration into the airway and activation appears to play a key role in the pathology of COPD. In contrast the inflammatory response characterizing asthma involves infiltration with activated eosinophils and lymphocytes. T-cell activation of the allergic response is also a key event.

Short-term advances in the asthma market will center on combination products. GlaxoSmithKline's bronchodilator-corticosteroid combination drug, Advair has been particularly successful offering improved efficacy and convenience. More recently, phosphodiesterase 4 (PDE4) inhibitors have received considerable attention, not only with respect to the treatment of asthma but also COPD, and this class of drug leads a new wave of therapeutics set to enter the airway inflammation market.

Cilomilast (Ariflo) is the PDE4 inhibitor that has been most fully tested in clinical studies, particularly in COPD, however its propensity to cause side effects has been a major concern. Indeed as highlighted in our tracking service DailyUpdates, the FDA has recently voted against the approval of cilomilast for the treatment of COPD due to doubts over the therapeutic window of this molecule. Roflumilast, looks more promising, as it has a more favorable therapeutic ratio and now the race is on to find a PDE4 inhibitor with lesser side-effects.

Emesis is the predominant side effect of PDE4 inhibitors due to their central effects. Known PDE4 inhibitors with emetogenic potential do not discriminate well between the catalytic (PDE4) and the rolipram binding site, respectively and experimental evidence suggests, that this, as well as low selectivity for PDE4A and PDE4B over PDE4D inhibition is related to the emetogenic potential of these compounds. AWD 12-281 is currently in clinical development phase 2a for the treatment of asthma, COPD and rhinitis. In a recent JEP article, Kuss et al characterize the pharmacology of this molecule in various models of airway disease.

In their publication, Kuss report that AWD 12-281, when administered to the airway, reduced allergic eosinophilia and LPS-induced neutrophilia in rats (ID50=7 & 0.02microgram/kg respectively) and in pigs (2 and 4 mg/pig). Likewise, AWD 12-281 when given intra-peritoneally also reduced neutrophilia in the ferret (estimated ID50=2.4mg/kg). Functionally, AWD 12-281 reduced both antigen-induced bronchoconstriction in guinea pigs and airway hyperresponsiveness in mice. The efficacy of AWD 12-281 against airway hyperresponsiveness was comparable to that of cilomilast.

Emesis was investigated in a variety of species. In the ferret, intraperitoneal administration of AWD 12-281 was well tolerated in doses below 15 mg/kg. With oral dosing behavioral correlates of emesis first became apparent at 30mg/kg. The minimal emesis-causing dose for cilomilast was 3 and 10mg/kg respectively. The low pro-emetic activity of AW 12-281 was confirmed in a prolonged inhalation study in dogs; at 14mg/kg for 4 weeks, AWD 12-281 was devoid of emesis and signs of nausea.

Hence, AWD 12-281 has been shown to be active in a variety of species and in various models of asthma and COPD. Importantly AWD 12-281 is active for prolonged periods of time when given intra-tracheally. In studies employing the same species and route of administration (ie ip dosing of ferrets) AWD 12-281 was more effective at reducing neutrophilia (estimated ID50=2.4mg/kg) than at producing emesis (minimal emesis-causing dose=15mg/kg). In these two assays the therapeutic efficacy of AWD 12-281 was similar to that of cilomilast, while AWD 12-281 was 5-fold less emetic. Given the efficacy of AWD 12-281 and its low pro-emetic side effects, further clinical data from patients with asthma or COPD treated with this PDE4 inhibitor are eagerly awaited.
Entry date Sunday, September 21, 2003

Adapted from Kuss et al, J Pharmacol Exp Ther. 2003 Aug 27 [Epub ahead of print]