Despite rigorous pre-approval testing of all pharmaceutical products, many approved drugs have serious and life threatening side effects that go undiscovered until the products have been launched and are in widespread use. ARYx's goal is to make these known therapeutic mechanisms safer by engineering out specific metabolic problems that cause toxic and dangerous side effects. Our novel drug products are carefully constructed and optimized to alter and improve metabolism while maintaining established efficacy.
Problems with Toxicity in Existing Drugs
Drugs are eliminated from the body by excretion generally through the urine or the bile. Some drugs may be excreted unchanged while others first undergo metabolism. How drugs are metabolized may have a direct impact on safety. Through a process of biotransformation, drugs are metabolized into other compounds, called metabolites, that are generally water soluble, allowing them to be easily excreted by the kidney or liver.
CYP450 is a family of naturally occurring enzymes, present primarily in the liver but also found in other organs, that are estimated to be responsible for the metabolism of approximately 90% of the drugs available today. The CYP450 system has evolved to break down the small amount of pharmacologically active or potentially toxic materials found in plants. This system has a low capacity and can process only small quantities of pharmacologically active substance at a time. In addition, certain drugs can inhibit the functioning of these enzymes while other pharmaceuticals induce the activity of the enzymes. When a person takes more than one drug at the same time, a potentially harmful competition results for the limited quantity of CYP450 enzymes. As a result, drug-drug interaction occurs because drugs are not able to be metabolized and instead remain in the body at elevated levels, potentially resulting in either on-target or off-target side effects. These unwanted side-effects are referred to as adverse drug reactions. For this reason, as reported by the FDA, the frequency of adverse drug reactions rises exponentially in patients taking multiple pharmaceuticals. For example, 80% of patients on the oral anticoagulant warfarin take at least one additional drug that interferes with its clearance. This is why warfarin use is the third most common cause of adverse drug reactions.
The increase in adverse drug reactions attributable to a patient taking several medications at the same time results from an increase in the circulating level of the drug in the body and the increased potential for a toxic effect either as a result of "over dosing" or an "off-target" effect. Altered drug level directly impacts the safety and efficacy of that drug. In order to be effective, a drug must circulate in the body in sufficient therapeutic levels to allow it to reach and impact its primary site of action. However, if the blood levels remain higher than required for the desired on-target pharmacological effect to occur, then a toxic side effect can result either due to the drug over-loading the primary site of action (exaggeration of "on-target" pharmacology) or due to the drug affecting another site of action, causing an off-target effect with potentially undesirable outcomes.
According to the FDA, it is estimated that over two million serious adverse drug reactions occur annually in the United States, resulting in more than 100,000 deaths. The FDA also reports that adverse drug reactions are the fourth leading cause of death in the United States, ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths. Complications caused by adverse drug reactions are estimated to increase health care costs in the United States by approximately $136.0 billion per year.
Our RetroMetabolic Drug Design ™
A key element of our process is to determine whether our RetroMetabolic Drug Design™ technology can be successfully applied to an existing drug that has safety problems. We apply our approach to reengineer drugs that are metabolized by CYP450. In order to apply our technology, our scientists fully analyze the existing drug's pharmacological mechanisms, attributes and potential liabilities. It is our scientists' proprietary knowledge of how to design a product candidate that retains the on-target pharmacological effects of the existing drug while primarily eliminating clearance through the CYP450 pathway and eliminating the most important off-target liabilities that allows us to make safer alternatives to existing drugs.
Unlike traditional drug discovery, our approach begins with a thorough understanding of the structure of an existing drug and leads to the creation of a new molecule through a series of unique steps. A key step in this process is the creation of a theoretical "ideal metabolite." The ideal metabolite is a nontoxic, water soluble, pharmacologically inactive compound that is not metabolized by the CYP450 pathway. As a result, our product candidates are designed to avoid the metabolic bottleneck of CYP450 mediated drugs and the resulting potentially dangerous build up of drug levels. This "ideal metabolite" is a novel chemical entity not created through the metabolism of the original drug.
The esterase system, which consists of enzymes that are widely available throughout the body, is the metabolic pathway through which our product candidates are converted into their "ideal metabolites." Once converted by the esterase system, our metabolized product candidates should be easily excreted from the body primarily through the liver and kidneys, avoiding competition from other drugs metabolized through the CYP450 pathway.
Once the ideal metabolite is engineered, our scientists build a series of new pharmacologically active molecules that are designed to break down outside of CYP450 into our ideal metabolite. Successful product candidates mirror the pharmacology of the original drug. This is why we call our approach "retrometabolic." We begin with an engineered inactive metabolite and then create a limited number of product candidates rather than screening tens of thousands of active molecules as is done in traditional drug discovery.
The product candidates engineered through our RetroMetabolic Drug Design™ technology are fully patentable new chemical entities. In our clinical trials to date, we have demonstrated that our approach to drug discovery maintains the established pharmacological effect of the therapies we are mirroring and utilizes an alternative non-CYP450 metabolic pathway that should avoid the drug-drug interactions and, with certain candidates, the off-target pharmacology of the original drug.
ARYx's goal is to make proven therapies safer.
