Readers of DailyUpdates, our daily tracker for the drug discovery sector (click here), or indeed anyone who follows advances in the pharmaceutical industry will be aware of major changes occurring in the field of asthma therapeutics. For example, Novartis announced on June 23rd that the novel IgE-blocker Xolair® (Omalizumab) has been approved by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe persistent asthma in adults and adolescents. At the same time Merck Sharp & Dohme announced that they have agreed to fund Amrad with an upfront payment of $7.4 million, and potentially up to $167 million plus royalties, to advance its early-stage biological treatment for asthma.

This activity is hardly surprising given that the incidence of asthma has dramatically increased over recent years. Furthermore, although currently available treatments are generally effective patient compliance that is currently very 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 Xolair 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 and up until recently annual growth rates of 10-15% have been reported. Most sources however predict that this level of growth is not sustainable. Competition within the anti-asthmatic market will therefore grow increasingly intense. In response to activity 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, LeadDiscovery has recently produce a state of the art of asthma therapeutics.

One of the targets analyzed in our asthma dossier is Syk tyrosine kinase. Syk (p72Syk) kinase is a protein tyrosine kinase that plays a pivotal role in high affinity IgE receptor signaling in mast cells. Syk is also involved in antigen receptor signaling of B and T lymphocytes and in eosinophil survival in response to IL-5 and GM-CSF and so Syk inhibitors might have several useful beneficial effects in atopic diseases. Aerosolized Syk antisense oligodeoxynucleotide inhibits allergen-induced inflammation in a rat model, indicating that this may be a target for drug development. Given this proof of concept it is exciting that Bayer researchers have recently identified BAY 61- 3606, a potent (Ki = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC50 values between 5-46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61- 3606 was highly efficacious in basophils obtained from healthy human subjects (IC50 = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50 = 8.1 nM). B cell receptor activation and IgE receptor signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Further, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk might play a very critical role in the pathogenesis of allergic reactions. Further development of BAY 61-3606 is eagerly awaited. On the other hand readers may be aware of the “Kinase Enterprise library” recently featured by LeadDiscovery. This is a targeted library of candidate kinase inhibitors that is available for in house screening and screening of this library for other inhibitors of Syk may be of immense benefit to companies involved in airway inflammation (Click here for further information on this library).

Entry date Thursday, July 03, 2003

Adapted from Yamamoto et al,J Pharmacol Exp Ther. 2003 May 23 [Epub ahead of print].

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk