Utilizing deCODE’s structural biology and medicinal chemistry capabilities, we have advanced three lead therapeutics programs into clinical development. These programs include DG041, which we are developing for arterial thrombosis, is a novel antiplatelet compound designed to inhibit platelet aggregation in a manner that does not increase bleeding time; DG051, an inhibitor of leukotriene A4 that targets a major inflammatory pathway for the prevention of heart attack; and DG071, a PDE4 modulator for the treatment of Azheimer’s disease and other cognitive disorders, and on which we have filed an IND.

DG041 is being developed as an anti-platelet compound for the prevention of arterial thrombosis. DG041 is a first-in-class small molecule inhibitor of the EP3 receptor for prostaglandin E2, a G-protein coupled receptor (GPCR). It has been demonstrated by in vitro studies that PGE2 may have additive stimulatory effects on platelet aggregation beyond those of other potent agonists such as ADP or thromboxane A2, targeted by clopidogrel and aspirin, respectively. The results of the Phase I program showed DG041 to be well-tolerated across the entire dose range studied, and to inhibit platelet aggregation in a dose-dependent manner without increasing bleeding time.

We completed a successful Phase IIa trial of DG041 along with a highly informative clinical pharmacology study conducted in the presence and absence of aspirin. We also completed key drug-drug interaction studies with DG041that demonstrated a lack of any relevant interaction by DG-041 on two common routes of drug metabolism. Based on the results of our clinical studies thus far, DG041 appears to be well-tolerated, showing little difference in bleeding events between dosing arms and placebo, and to potentially offer focused means of preventing the formation of thrombi by specifically inhibiting platelet aggregation mediated by EP3. In 2008, we completed a second clinical pharmacology study examining the impact of DG041 on top of aspirin and Plavix TM, the results of which show that DG041 blocks platelet aggregation and does not increase bleeding time when given alone, with Plavix TM, or with Plavix™ and aspirin. We are concurrently on a controlled release formulation for DG041.


We have two compounds in development for the prevention of heart attack, DG051 and DG031. These programs build upon our discovery of major risk variants for heart attack in two genes encoding proteins in the leukotriene pathway. These variants – in the genes that code for leukotriene A4 Hydrolase (LTA4H) and 5-lipoxygenase activating protein (FLAP) – appear to confer risk in the same way: by causing an up regulation in the production of leukotriene B4, a potent pro-inflammatory molecule that is the end product of one branch of the pathway. The therapeutic goal of both compounds is to inhibit the activity of the pathway, lowering the production of LTB4 and thereby decreasing the inflammatory activity in atherosclerotic plaques and reducing the risk of heart attack. In addition to reducing the risk of heart attack, these drugs may provide benefit in other inflammatory diseases.

Discovered internally by deCODE’s chemistry unit, is a small-molecule inhibitor of LTA4H, which is directly involved in the synthesis of LTB4. In 2007, we completed our Phase I program, the results of which demonstrated that DG051 was safe and well tolerated at all doses tested, has a pharmacokinetic profile suited for potential once-a-day dosing, and significantly reduces LTB4 levels in a concentration-dependent manner. Early in 2008 we announced the results of a Phase IIa study the results of which demonstrated safety and tolerability and a significant reduction in LTB4, even at lower doses than were originally considered.

deCODE has also in-licensed a FLAP inhibitor from Bayer AG, now known as DG031. Our Phase II clinical studies demonstrated that DG031 was well-tolerated and reduced production of LTB4 in a dose-dependent manner. This effect was seen on top of the effects of the current standard of care, which included statin therapy for a majority of patients in our trials. In 2006 we began a Phase III clinical trial for DG031, a trial which we voluntarily suspended because the drug tablets appeared to dissolve more slowly than anticipated, potentially providing lessening amounts of active drug the longer they were stored. We have successfully reformulated the compound.

DG071 is a novel, potent and selective PDE4D modulator discovered by deCODE’s chemistry group. First and second generation PDE4 inhibitors such as rolipram, cilomilast, and roflumilast caused significant side effects, including nausea and vomiting, at therapeutic doses in human clinical trials. Such side effects severely limit the utility of these earlier compounds. Data generated at deCODE suggest that the observed side effects were closely correlated with the binding of these molecules in the PDE4 enzymatic active site competitively with cAMP.

As cAMP is of critical importance to neuronal signaling, the goal of deCODE’s program has been to discover compounds that would modulate PDE4 activity via an allosteric mechanism to improve safety and tolerability. Towards this goal, the deCODE biostructures team solved multiple novel co-crystal structures of PDE4D & PDE4B containing regulatory domains with bound ligands. Those structures allowed the deCODE chemistry team to identify a novel binding site for allosteric modulators in the PDE4 regulatory domain. Binding of an allosteric modulator at that site is non-competitive with cAMP. DG071 has been shown in animal models to improve cognitive function with benefit similar to that of cholinesterase inhibitors such as donepezil that currently are a mainstay of therapy for memory loss in early Alzheimer’s disease, yet also benefiting long term memory function in animal tests where the cholinesterase inhibitors are ineffective. Additionally, we have developed a broad proprietary platform for PDE4 modulators that we are applying to discover compounds with potential utility for the treatment of over-active bladder, inflammatory and respiratory diseases.

The DG071compound is being developed as a new and potentially safer means of targeting PDE4 to combat memory loss and cognitive deficits associated with Alzheimer’s disease and other disorders in which neural signaling is reduced or impaired. In animal models, DG071 has been shown to significantly improve learning and long- and short-term memory at doses that offer a wide margin for safety and tolerability. The compound has the potential to eliminate the nausea that limits the utility of previous PDE4 inhibitors. In October 2008 we filed an IND application for DG071.