New Technologies to Help Weather the Storm

With the rising costs of research and development, the introduction of innovative technologies to increase the overall effectiveness of drug discovery remains critical. However, with so many technologies to potentially invest in and constrained research budgets, the challenge is to identify those which will have the greatest overall impact on the pipeline.

Despite the difficulty in predicting the overall return on the investment, we’re seeing more R&D groups buying in solutions rather than trying to do everything themselves. In addition to academic groups performing basic or translational research , vendors/ CROs and biotech companies are offering an increasingly wide range of capabilities – from generic services to those that are too specialized for p harma to invest in internally.

For NCE discovery, we are seeing a growth in risk-/profit-sharing partnerships – in contrast to conventional outsourcing aimed at reducing costs and allowing internal research groups to focus on value-added activities. The purchase of companies specializing in biopharmaceuticals, such as monoclonal or domain antibodies or nucleic acid therapeutics, is opening new avenues for large pharmaceutical companies to pursue targets that were previously considered intractable for small molecule intervention.

Future focus

Research teams are also focusing more on using pharmacogenetics and well-characterized diseases to define smaller, more-directed and stratified patient populations for clinical trials. After the initial transition i nto the market , subsequent research into additional indications can grow what can initially be a relatively small product . A t all stages of research – from the initial selection of the target through to later development – there is a much greater focus on the need for product differentiation compared to what is predicted to be on the market. This is forcing research teams to seek out more novel unprecedented targets although that necessarily increases the risk that the candidates will not prove effective in the clinic.

Technological advances

One approach to mitigate some of this risk is the more widespread use of human primary, rather than recombinant and/or rodent, cellular systems for target identification/validation and lead optimization. Since these cells do not have the same reporter gene constructs as many conventional assays, there has been a need for a parallel evolution in the assay technologies used – with a greater focus on high content imaging, measuring cellular phenotypes and monitoring endogenous signaling pathways. Software companies are now providing well-annotated databases summarizing the known properties and literature surrounding many important signaling pathways – information which can greatly help in establishing relevant biological assays in primary cells and interpreting the data.

While the use of primary cells and endogenous readouts is certainly not new, cell culture , automation and assay technologies have advanced over the past few years so that we can combine much of the throughput and robustness of conventional recombinant cell-based assays with the physiological and biological relevance of human primary cell s. This allows these more native systems to be used earlier in discovery , for high- throughput screening with more than 1 million compounds in some cases.

However, there remains a long way to go before we can provide authentic cell-based assays for all disease areas; for example , in neurosciences the availability of primary cells and the ability to mimic complex cellular interactions remains a particular challenge.

Stem cells will likely become increasingl y important for deriving difficult to obtain human tissue to use for research purposes , while the use of co-cultures or 3D cultures containing different mixtures of cell types should in principle better replicate in vivo systems.

The momentum in this field is growing rapidly . While it can only hope to incrementally reduce th e risk of attrition in the clinic, the more widespread use of cell-based assays that ar e more pathophysiologically relevant than those used in the past should prove valuable for many , if not all , therapeutic areas. 

Across R&D , we need to continue to be aware of what’s available externally , and then be able to augment that with complementary internal skills and capabilities. To meet some of the challenges facing research, new technologies that significantly improve the selection and validation of targets and compounds will continue to be sought , whether they are developed internally by p harma ceutical companies or , increasingly , provided by vendors, biotech or academia.

About Keith Moore

In his role as VP of Discovery Technology at GlaxoSmithKline in North Carolina, Keith Moore is responsible for deploying genetics, chemical genomics, biomarkers and cell biology to support target identification/validation and compound progression up to candidate selection. His previous experience was in assay development for HTS and uHTS.