Lead Compound (CDX-085)

Cardax Pharmaceutical's lead small molecule compound is being targeted initially for reduction of oxidative stress and inflammation associated with dyslipidemia and metabolic disease.

Other potential indications driven by oxidative stress and inflammation include rheumatoid arthritis, recurrent thrombosis, oxidized LDL and atherosclerosis, and liver disease.

Lead Compound Rational
Most therapies for the reduction of triglycerides have issues of safety or convenience. The fibric acid derivatives have known risks of adverse effects when used in combination with statins. Newer drugs such as purified derivatives of the omega-3 fatty acids must be taken at very high doses (4 grams per day) and some increase LDL. Our lead compound not only shows significant triglyceride-lowering capability at much lower, more manageable doses, but lowers key markers of inflammation such as TNF-a and raises HDL and adiponectin. Reduction of very high triglycerides is a direct and efficient pathway for FDA approval of a new drug.

Metabolic syndrome has been well-characterized by the consensus of multiple expert panels and organizations and identified as one of the largest, rapidly increasing threats to world health. A key component of this syndrome is dyslipidemia that includes moderate to severe elevation of triglycerides. While not yet an approved label indication in the U.S. currently, metabolic syndrome most likely will have to be considered as a label-worthy indication by regulatory commissions in the future.

The arthritis market is very large at approximately $35 billion annually, of which $18 billion are the injected TNF-a inhibitors, according to the 2008 Global Market Arthritis Review. New oral anti-inflammatory compounds targeting other pathways, such as JAK, are expected to be approved, growing this market even further. All of these anti-inflammatory compounds suffer from meaningful side effect issues when administered chronically. In contrast, the active drug of CDX-085, astaxanthin, reduces TNF-a equivalent to steroids, the gold standard of anti-inflammatory compounds, in animal models and does not have the immunosuppressive effects of steroids or TNF-a inhibitors. In fact, no dose limiting toxicity for oral administration of CDX-085 in animals has been found. Dietary supplement forms of astaxanthin, which should be predictive of CDX-085 efficacy in humans, lower TNF-a in a clinically meaningful way, even at very low, ultra-safe doses.

Rethrombosis, a major risk for people who have had acute coronary syndrome or an ischemic stroke. The goal of therapy following thrombosis is to maintain arterial patency and to preserve the area of reduced perfusion in the heart or brain. In thrombotic stroke, for example, 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 (or “rethrombosis”) is a novel and relatively 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 is a major contributor to the pathophysiology of rethrombosis; therefore, while the Company is focusing first on triglyceride reduction and metabolism with its proprietary lead compound, on rethrombosis and related platelet aggregation following ischemic stroke, where animal models have been particularly predictive of human efficacy, remain of significant interest.

Astaxanthin, the active metabolite of the lead compound completely spans the lipid component of the cell membrane facilitating its anti-oxidant and anti-inflammatory effects. X-ray diffraction examined 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 within cellular membrane, including mitochondrial membrane, drives the reduction of 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.

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 drug of CDX-085:

• 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).