A new model for drug discovery

The productivity crisis in pharmaceutical drug discovery, or ‘innovation gap’ as it has been coined, is well recognised and the subject of much debate in the industry and spectator commentary.

“The existing pharma discovery paradigm needs to be supplemented with a complementary strategy”

With only 18 NCEs approved in 2007, and an average cost of developing a single NCE now exceeding $1billion, the pharma R&D model is arguably unsustainable in its current form. In comparing the productivity of the industry over the last several decades it is useful to consider the evolving drug discovery paradigm during this period. Within the last 20 years the drug discovery paradigm has increasingly embraced a central dogma for discovery that is recognised today as ‘target based medicinal chemistry’.

Central to this paradigm are the well-recognised and structured stages of early drug discovery, including target identification, high throughput screening, and lead optimisation efforts. Prior to this period, the industry discovery paradigm was not as well organised and much more subject to serendipity. Contrary to widely held expectations, the modern paradigm has delivered the lowest rate of new drug approvals in a generation. 

It is important to note that target based drug discovery, is a hypothesis-based approach.   These hypotheses have their origins in an existing collective knowledge base that we must now accept is incomplete. Although the post-genomics era heralded the discovery of a plethora of ‘new’ molecular targets, there remains a very poor understanding of the spectrum of biology influenced by any given target. For any given protein receptor, for example, our understanding of the biochemical pathways does not begin to describe the complex interactions in that pathway that may be biologically relevant, neither is there a complete appreciation of the putative target’s influence on intersecting pathways. This statement is certainly true in a simple cell-based system yet the complexity of these interactions rises exponentially when we consider a fully assembled organism.

In a pharmaceutical R&D environment this biological complexity, and associated incomplete knowledge, manifests itself in the high attrition rates associated with drug development. It further reveals itself in the form of unexpected beneficial effects such as the analgesic properties of the gabapentinoids in neuropathic pain and the many pleiotropic effects of the statins.

Melior Discovery proposes that, in consideration of the limitations of the current industry central dogma, the existing pharma discovery paradigm needs to be supplemented with a complementary strategy that offers the potential to more rapidly and efficiently identify alternative beneficial activities. Given the apparent limitations of target based drug discovery, there is a compelling rationale for an approach that is not constrained by the aforementioned knowledge gaps. 

Melior Discovery has developed a platform for the optimal phenotypic screening of large numbers of compounds. TheraTRACE, is comprised of approximately 40 animal models of disease representing a very broad therapeutic area spectrum. Normally, the proposition of screening a compound across 40 sophisticated animal models would be deemed impractical. However, the company has succeeded in making the largely impossible, possible by developing a means to ‘multiplex’ animal models without compromising the quality of the underlying models. By taking therapeutic candidates, and systematically screening them across 40 models of disease, Melior has adopted a form of non-hypothesis-driven drug discovery. Only in this way is it possible to uncover otherwise truly unpredicted biology associated with a compound. Further, by screening in clinically relevant preclinical models of disease, this approach uncovers the most salient unpredicted biology as opposed to generating less useful phenomenology.

Very often, the unexpected biology is of therapeutic relevance and has been the basis of Melior’s drug repositioning efforts. Indeed, in a relatively short time, the company has built its own pipeline of therapeutic candidates repositioned from a library of drug candidates previously developed for other indications. 

Increasingly, pharmaceutical companies are adopting this approach and partnering with Melior in order to profile discontinued compounds as well as preclinical candidates in order to fully explore the pharmacological fingerprint of compounds destined to enter the clinic.

Andrew Reaume, Ph.D., MBA, is President & CEO of Melior Discovery, Inc., which he co-founded in 2005 with Dr. Michael Saporito. Prior to Melior, Dr. Reaume held positions of increasing responsibility at Pfizer Global Research and Development. Dr. Reaume received a Ph.D. in genetics from the University of Connecticut and an MBA with honors from the Wharton School.