Introduction

Selective metabolite compound product (SMCD) is a novel new drug discovery platform by means of identifying botanical drug metabolites in the body to develop new drug. The therapeutic value of traditional Chinese medicine has been widely recognized worldwide, however, it is still very difficult to emerge into the western mainstream drug market because traditional Chinese medicine is often a multi-component product without clear chemical composition and efficacy. Due to traditional Chinese medicine chemical composition of the highly complex nature, traditional Chinese medicine is not considered as the mainstream of modern Western medicine.

Pegasus’s proprietary Selected Metabolite Compound Drug (SMCD) technology is a novel drug discovery platform based on the findings that –

• 99% of ingredients in TCMs cannot be traced in blood after digestion, and those that can be traced are most likely to be responsible for the efficacy.
• Many active components of TCM traceable in the blood are metabolites, modified and activated in the body through body’s metabolic system, including intestinal and liver metabolic systems. They have their chemical structures changed either before absorption in the intestine or after absorption in the liver, or both. Therefore, tracing the metabolites of TCM in the blood may lead to discovery of new drugs.

Theoretical basis of SMCD has the following principles: (a) currently, study of proprietary Chinese medicine is more focused on the role of the combination of herbs and the proportion of each component, as well as the claimed clinical efficacy, rather than indentifying active ingredients and their levels. The rational combination of the components can enhance the efficacy and reduce the side effects. Therefore, SMCD, a multi-compound drug, is an optimized combination of several identified active constituents with a clear mechanism of pharmacology. The synergistic actions of the combination fully play its multi-target, multi-pharmacological action of the mechanism, and its potency. (b) SMCD concept requires the active ingredients must have a clear chemical structure, can be more readily chemically identified and quantified as well as the drug product is of consistently good quality with adequate in-process control and cGMP compliance. (c) SMCD requires that the standard pharmacokinetics study of principal active ingredient can substantiate its absorption, distribution and metabolism regarding systemic exposure. In addition, advanced analytical technologies can be applied for indentifying individual active ingredient and well characterizing its biological activity, and further interpreting the relationship between function target and each active ingredient. So that can ensure the drug product is indeed "safety, efficacy, quality and potency". (d) "clinically proven efficacy is the clincher", SMCD propose to completely change the traditional Chinese medicine drug discovery process that previously regulatory approaches are more interest in preclinical studies other than human clinical studies. Clinical trials of new drugs will be focused and centered in traditional Chinese medicine drug discovery.

How can traditional Chinese medicine paradigm as an integrative and systematic therapy and the concept of combination of herbal formula be adopted to the development and modernization of Chinese herbal medicine today, it is a challenge yet to be faced. The reason is that traditional Chinese medicine including patent Chinese medicine itself, has many inherent problems, such as complex nature of composition, the active constituents not identified and quantified as well as not consistently good quality, its biological activity not well characterized, and standard pharmacokinetic measurements, such as absorption, distribution, metabolism and excretion, for active constituents may be infeasible due to the complexity of the botanical drug. The existence of these problems has greatly hampered the traditional Chinese medicine to the world.  The modernization of traditional Chinese medicine should first solve the important issues and challenges.

In other words, SMCD Platform considers the body as a biological filter and converter-activator, which eliminates 99% of useless components in TCM, and then chemically converts those left into an active form. SMCD Platform traces and collects those metabolic compounds as new drug candidates. New drug developed using this approach is often a multi-compound drug which is much simpler than the original TCM formula. SMCD can be equal to, or even more efficacious and safer than the original TCM formula. SMCD is controllable in quality and compliable to GMP requirements because all the components in an SMCD are identified and characterized. SMCD might also lead to discovery of single-molecular entity drugs.

SMCD Platform is a valid approach to developing new drugs from the wealth of TCM formulae library. Key components of the SMCD technology have been filed for patent in 2004. Using this platform, Pegasus has already produced a series of products and product candidates.

Products Developed on the SMCD Platform

More than 60% of all TCM active components are thought to be in the category of saponins. Saponins are also the major medicinal ingredients in ginseng and many other plants. After intake, most of the sugar moieties in saponins are removed in the intestine metabolic system and absorbed into blood as sugarless metabolites, called aglycone sapogenins. Two major metabolites are aglycone protopanaxadiol (aPPD) and aglycone protopanaxatriol (aPPT). Researches have found that aPPD has strong apoptosis induction effect on cancer cells while aPPT can prompt the immune system to attack cancer cells with high specificity. The combination of aPPD and aPPT is our new drug candidate PandiMex™. It is obvious that aPPD and aPPT can also be developed into single compound drugs. Pegasus and its affiliated companies use proprietary chemical process to produce aPPD and aPPT directly from natural materials, bypassing the body’s metabolic system. The composition of the product is clearly identified and characterized, highly consistent and controllable. The two major single compound components have been proven to have multiple pharmacological targets and complementary effects.  CanaQ (Careseng® SG2) and HemoMex (PandiMex™) have been approved as anticancer drugs in Republic of Georgia. Careseng® line of products, Careseng RH, SG, SG2, BFG, AllerQ and Bioseng #1, are also available as natural health products approved by Health Canada.