Biotechnology in Drug Discovery

Biopharmaceuticals make up just 10 percent of the therapeutic market; the other 90 percent are SMOLs, also called drugs or pharmaceuticals (Cohen 2015). Unlike biologics, the chemical synthesis of drug compounds leads to exquisite reproducibility and low production costs. SMOLs are commonly identified by high-throughput screening of structurally diverse chemical compound libraries. Forward, also called phenotypic, screens identify lead compounds based on their ability to modulate a target phenotype (e.g., cell division) in vivo; specific targets are not known at the onset of the experiment. Conversely, reverse screens start with a well-characterized target and identify lead compounds based on their ability to modulate it in a relatively pure (and often in vitro) system. In both cases, standardized bioassays are used to assess phenotype/target modulation.

Although not required for production, biotechnology is essential for drug discovery. Most notably, biotechnology is used to identify and characterize drug targets, provides bioassays for high-throughput screening, and streamlines efficacy/toxicity testing required for federal approval.

The steps taken to develop a new drug are collectively called the drug discovery pipeline.24 On average, the process—that is R&D, preclinical animal testing, and multiple phases of clinical human testing—takes a decade25 and $2.6 billion dollars (Mullin 2014). R&D costs are massive; 80 times greater than the expense 60 years ago, with only 1 in 10,000 lead compounds ever making it to the market (Blank 2013). Most leads fail between preclinical and Phase II clinical trials, an area of the drug discovery pipeline referred to as the valley of death. A rare new drug introduced to the clinic must bankroll the 9,999 projects that were abandoned along the way, consequently driving up the cost of all pharmaceuticals. The more personalized the treatment and the smaller the patient pool, the greater the cost per patient.

Box 3.5. The price of precision

Although potent and efficacious, biologics are extremely expensive due to complex biomanufacturing procedures that must be strictly adhered to for quality and safety assurance. Where the average drug therapy costs $1 per day,26 biologic treatments cost $22/day (McCamish and Woollett 2011). Apply this to chronic diseases, and patients are faced with astronomical medical expenses. Herceptin treatment for breast cancer costs ~$37,000 per year (McCamish and Woollett 2011). Patients with the chronic gastrointestinal disorder, Gaucher disease, are faced with mAb treatment costs of ~$200,000 per year, every year, for the rest of their lives (McCamish and Woollett 2011).

How can this situation be rectified? Addressing bottlenecks in the R&D/approval pipeline will reduce the price of all kinds of therapeutics. A greater understanding of biologics and their intended (and unintended) actions will promote the development of lead-on biosim- ilar—or even biobetter—therapeutics with lower production costs and enhanced efficacy. Fast-tracked federal approval processes will make the development of biosimilars more attractive to biopharmaceutical companies. Perhaps even the development of synthetic organisms, with simplified regulatory and metabolic pathways, may offer streamlined production protocols that translate to lower patient costs.

The rigor of the drug discovery pipeline necessitates that a series of stakeholders tackle different parts, each doing their own specialized job to move candidates forward. Targets, hits, and leads are primarily the work of academia and small biotech. Much of the initial drug discovery costs are supported by public and private grants to individual principle investigators.27 Promising leads may be picked up by big biotech and large research foundations at the level of animal and human clinical trials. Collaboration between these groups is critical for success.

In addition to better communication between stakeholders, the Phase II-associated bottleneck may be overcome by improved preclinical models of disease. Computational, tissue culture, and animal models are supported by system-based approaches, those that are informed by pharmacogenetics and leverage ‘omic, transgenic, and stem cell technologies. The introduction of killer experiments, intended to disqualify early leads based on toxicity or limited efficacy, will support the pursuit of higher quality—not quantity—leads. Doing so will reduce R&D costs to drug developers; savings that will trickle down to consumers. Furthermore, the development of better diagnostics will support Phase II efforts by identifying appropriate subjects for trials and more accurately assessing the impact of treatments. Taken together, Next Gen biotechnologies have the potential to transform the current state of drug discovery.

Box 3.6. Challenge application exercise: Product portfolios

Visit the websites of five leading U.S. biotech companies—Gilead Sciences, Amgen, Biogen, Celgene, and Regeneron. What are their headline biopharmaceuticals? What treatments are in the R&D pipeline? Categorize each biologic as a purified protein, mAb, gene therapy, or cell/tissue replacement. Do these companies mainly address infectious, genetic, or multifactorial diseases? How do their product portfolios align with what you’ve learned about blockbuster drugs and orphan diseases? Once you have a feel for these industry leaders, visit the website for a premiere philanthropic organization—e.g., The Bill and Melinda Gates Foundation. How do the goals, projects, and activities differ from those of the commercial sector?

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