Perspective on Systems Pharmacology: When multi-targeting is advantageous
The safety and efficacy of therapeutic drugs still requires improvement. In part this is due to the promiscuity of individual drugs, which on average can interact with an estimated 6-28 other off-target moieties.
However, the advent of both systems biology and precision medicine has stimulated a rethink on the process of therapeutic drug design and polypharmacology. More recently, the definition of polypharmacology has morphed to represent therapeutic drugs that have been designed deliberately for multi-targeting that affords beneficial effects to the patient. This emerging effort has been labelled ‘Systems Pharmacology’ and the products are referred to as multi-target or systems pharmacology drugs.
The current Drug Discovery and Development (DDD) paradigm was conceived in the early 1960s and has remained relatively unchanged over the past ~60 years. We, and others, have argued that this continues to be a risk-laden, slow, costly and inefficient process, as well as delivering products of questionable value in terms of safety/toxicity and efficacy (1-5). For example, significant cumulative risk is associated with any effort to bring a candidate drug to market.
The initial screening of compound libraries (104-106 candidates), leads to a single lead compound that has only an ~8% chance of successfully traversing the clinical trials gauntlet (6). In addition, the failure rate of a drug candidate at each clinical trial phase is reported to be 46% (Phase I), 66% (Phase II) and 30% (Phase III) (4). The average time required from drug discovery to product launch remains an eyewatering 12-15 years (5). In addition, the total capitalised cost of bringing a new drug to market was recently estimated at a staggering $2.87 billion (7).
The metrics associated with the DDD process are clearly problematic. There is also a concern about the safety and efficacy value proposition of current marketed therapeutic drug products produced by the current DDD process...
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