The 21st Century Gold Rush: Novel Molecular Targets

Of the 113 first-in-class drugs approved by the FDA between 1999 and 2013, target-based research approaches accounted for 69% of discovered drugs ⁽¹⁾. The target-based approach is hypothesis driven with the goal to modulate a biological component within a disease system. With so much R&D focus on precision medicine, this percentage is poised to continue to increase as drug development trends toward smaller patient subpopulations, or disease systems, versus the antiquated one-size-fits-all model.

Target identification is the first step to discover the next first-in-class and potential-blockbuster drug. Although the human genome comprises approximately 30,000 genes, as of 2013 proteins encoded by only about 400 genes are current drug targets ⁽²⁾. Newer drug-discovery technologies such as Alnylam’s RNAi and Moderna’s mRNA platforms have made it possible to explore modulating previously considered “undruggable” biological targets. This technology however does not take away the importance of choosing the right target to begin the drug R&D lifecycle.

As part of the target identification process, understanding the molecular mechanisms of disease is of fundamental importance to increase the confidence in target selection. Systems biology methods using multi-omics level data can help explain the complex interplay of biological signals.

Immuno-oncology is another competitive R&D field and the poster child for where selecting the proper target has translated into high rates of clinical success and better outcomes across a number of oncology indications. Novel immuno-oncology targets are continuously emerging that build on the mechanistic understanding of processes such as immune-checkpoint inhibition. Two of the most well studied targets are CTLA-4 and PD-1, which activate the immune system upon signaling blockade by a drug. Pathway-based approaches can bring together immuno-oncology related targets in a signaling context while also providing a template to understand the potential next generation of novel targets in this area (Figure 1).

FIGURE 1: Immuno-oncology targets highlighted in this Nature review article and visualized using MetaCore (4)

Properly identifying novel targets for drug development can quickly bring a substantial return on investment. Lead molecule and preclinical compounds have become a more attractive asset for pharmaceutical companies to acquire or collaborate on. Since 2014, discovery and preclinical deals rose from a five-year average of just 9 percent to 22 percent of total deals over each of the past two years (Figure 2). These early stage partnerships usually include future milestones that are more likely to come to fruition positioned on the strength of the initial target selected.

FIGURE 2: Percent distribution of lead product stages for therapeutic product company mergers and acquisitions

So how does a carefully selected target translate in the clinic? The primary reason for phase 2 and phase 3 clinical trial failures are due to a drug’s lack of efficacy ⁽³⁾. Digging deeper into the pitfalls within clinical trials, AstraZeneca quantified that the lack of clinical efficacy was primarily driven through poor target selection (Figure 3). Although many other factors contribute to clinical success, all these essential R&D steps fall downstream and many years and dollars after that initial, critical step of target identification and selection.