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Perspective on Systems Pharmacology: When multi-targeting is advantageous

Perspective on Systems Pharmacology: When multi-targeting is advantageous

By Dr Kirkwood A. Pritchard Jr, Dr Dustin P. Martin and Dr Stephen Naylor
Winter 2018/19

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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