Lead Compound

Cardax Pharmaceutical's lead small molecule compound is designed to reduce oxidative stress and inflammation associated with pathological thrombosis and related platelet aggregation.

Other potential indications targetting oxidative stress and inflammation in cardiac tissue include atrial fibrillation, reduction of oxidized LDL, or reduction of PCI associated myocardial peri-procedural damage (i.e. cardioprotection).

Compound Rational
Rethrombosis is the major risk in at least 3 million of the more than 5 million people in the U.S. who have had an ischemic stroke. Cerebral artery occlusion from thrombosis is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. The goal of therapy following thrombosis is to preserve the area of reduced perfusion. In the most recent Treatment Guidelines, tPA is the only recommended therapy. Regardless of current treatment modality, the re-occlusion, or rethrombosis rate, is high, estimated at 30% overall in the first 30 days. A majority of the re-occlusive events occur within the initial 7-10 days post treatment.

While therapies targeting “stroke” and in particular brain salvage (i.e. neuroprotection) have had limited clinical success, the Company believes that prevention of the reformation of blood clots is a novel and efficient pathway to human proof of concept and eventual FDA approval for this indication. Lysing blood clots has already proven helpful (with tPA and other thrombolytic agents) and prevention of rethrombosis can be measured, as a human proof of concept, in a statistically significant and clinically meaningful way.

Oxidative stress contributes to the pathophysiology of rethrombosis; therefore, the Company is focusing first, with its proprietary lead compound, on rethrombosis and related platelet aggregation following ischemic stroke, where animal models have been particularly predictive of human efficacy.

The lead compound was efficacious in a clinically relevant canine model of carotid artery rethrombosis and platelet aggregation. Treated animals exhibited statistically significant alterations in reocclusion rate and rethrombotic pathology, without affecting hemostasis. These results provide a rationale for the design of a human proof of concept study in patients with ischemic stroke. The lead compound is undergoing pre-clinical development and is expected to be ready for human clinical trials in 2009.

Astaxanthin, the active metabolite of the lead compound spans lipid component of the cell membrane facilitating its anti-oxidant and anti-inflammatory effects. Recently performed X-ray diffraction looked at five antioxidants and showed clearly that each one orients differently within the cell membrane (Fig.1). This difference may explain why apolar antioxidants like beta-carotene, Vitamin C and Vitamin E have not achieved clinical success. Astaxanthin's localization as well as its antioxidant and related anti-inflammatory properties reduce the oxidative stress that initiates and/or perpetuates the chronic and pathological activation of a number of inflammatory pathways, including NF-KB.

Fig. 1 Representative X-ray diffraction data illustrating the effect of carotenoid structure on orientation and localization within biological membranes. Unlike apolar carotenoids such as beta-carotene, astaxanthin is a polar carotenoid

Safety
Safety is a critical aspect of drug development in the current regulatory environment. Most drugs target highly specific biological enzymes or receptors such as COX-2, TNF-α, CCR2, etc. While these natural targets play a significant role in inflammation, they are also critical components of important other biological pathways. With chronic use of these drugs, these pathways may not function normally, resulting in adverse events. Also, these treatments often negatively affect other crucial biological systems, creating additional off-target side effects.

Astaxanthin, the active metabolite of the lead compound:

• Localizes in the plasma, mitochondrial, and nuclear membranes;
• Scavenges or quenches the unwanted initiators and perpetuators of inflammation - reactive oxygen and nitrogen species (ROS and RNS); and
• Decreases infections in animals; with
• No evidence of off-target effects (e.g. receptor or pathway).