Guest Commentary: Academic institutions play active role in early-stage drug discovery process

In the past decade, the role academic intuitions play in drug discovery has evolved, with more emphasis being placed on finding the chemical compounds that can modulate that promising target.

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In 2007, pharmaceutical giant Merck created a department called External Basic Research to actively seek partners for early stage drug development. Their ultimate goal is to produce as much as 25 percent of their drug pipeline through this program. They are not alone. Over the past few years, a growing number of pharmaceutical and biotechnology companies have begun outsourcing basic research so they can focus more intently on medicinal chemistry, pharmacology and other processes further downstream in the drug discovery process.

There is fundamental market logic behind these moves. As our ability to identify potential drug targets has grown, the intrinsic value of each individual target has decreased. As a result, drug companies have pared back expensive basic research programs and reallocated those resources. Of course, the question is: who is going to pick up those early pipeline investigations? While there is no single answer, it is clear that academic institutions are playing an increasingly important part in early-stage drug discovery.

The role of academia
Most investigators in an academic setting focus on basic biomedical research. These scientists are working to answer fundamental questions about human biology and to identify which biological pathways are relevant to disease. Historically, if a promising target was identified, that knowledge could be licensed to a for-profit company for further development, and then, possibly clinical trials.

However, in the past decade, the role academic intuitions play in drug discovery has evolved, with more emphasis being placed on finding the chemical compounds that can modulate that promising target. A number of institutions have invested heavily in chemical genomics, opening high-throughput chemical compound screening facilities to augment their basic science investigations. These facilities provide advanced chemical and image-based screening capabilities, which until recently were more often found at large pharmaceutical companies.

While academic institutions began investing in chemical genomics and other advanced technologies, the National Institutes of Health (NIH) created its Roadmap for Medical Research to fill gaps in the research pipeline and transform how biomedical research is conducted. These two paths intersected in 2008, when four basic research institutions were awarded NIH contracts to become comprehensive screening centers as part of the Institutes' Molecular Library Probe Production Center Network. Under this program, the sophisticated screening technology at the four centers, combined with the NIH's 350,000 compound chemical library, was made available to researchers at academic institutions around the nation. With these tools, scientists who had previously been restricted to target identification were now enabled to develop chemical probes that they could use to illuminate biology. In some cases, these probes have proved to be promising chemical leads that might eventually generate new classes of medicines.

Academia and pharma

With these new capabilities, a number of academic research institutions are poised to take a more active role in the drug discovery process. However, what has yet to be completely worked out is how academia and industry will work together under this new model.

First, we must recognize that the science being conducted at academic institutions is fundamentally different from that being conducted at most pharmaceutical companies. In an academic setting, the goal is discovery and ultimately publication. On the other hand, a for-profit drug company is primarily concerned with finding new drugs, and hopefully, profit. While many excellent publications have come from drug company research labs, these papers were more a byproduct of the research process and not the end goal.

While academic researchers are also hopeful that their work will lead to new treatments, they take a more incremental, less directed, approach than their colleagues in the pharmaceutical industry. This can be very advantageous in the early discovery phases because investigators are not wedded to a specific direction, opening the door for serendipitous outcomes.

For example, a great deal of research has been focused on understanding the pathways behind apoptosis, or programmed cell death. Understanding apoptosis and identifying potential drug targets within that process is highly relevant to oncology, as many cancer treatments are designed to instigate the selective death of aberrant cells.

On the other hand, neurodegenerative diseases require the opposite approach. For patients in the early stages of Alzheimer's, Parkinson's or Huntington's disease, or those who have suffered a recent stroke, the ability to preserve cells that are destined to die would have great therapeutic benefit. As a result, understanding the biochemical equilibrium that keeps cells alive in cancer can easily cross over to research on numerous neurodegenerative diseases, and vice versa.

Can pharmaceutical companies take advantage of these peripheral outcomes? They certainly can, but whether they should invest further time and resources into advancing the research depends on many issues, including whether they even have a disease-focused division in which the target fits. Because academic researchers are generally not wedded to a specific therapeutic area or disease, they are better positioned to exploit the discoveries that they make. Also, as new data becomes available, they have the flexibility to follow up on the new direction and seek partners who share this research interest.

On the other hand, while pharma companies are increasingly moving away from basic research and target validation, they have retained strong core capabilities in medicinal chemistry and pharmacology, which they augment with outsourcing, to rapidly move lead compounds into clinical candidates. Most non-profit academic institutions lack the financial resources necessary to move a lead that far downstream, let alone enter preclinical or clinical trials. But even more importantly, they are not currently set up to pursue that type of research, as it does not match their mission of uncovering the fundamental biological underpinnings of disease.

A complementary relationship
In essence, the foci of research at academic institutions and pharmaceutical and biotechnology companies are inverse, with the academic side stressing the earliest stages of discovery and the pharmaceutical companies hungry for compounds that fit their disease focus and that can be moved rapidly down the pipeline to market.

So the beauty of this evolving relationship between academia and pharma is the complement of their strengths. Because industry has moved away from basic research, they are increasingly reliant on academic institutions to develop and validate new targets and to screen these targets for hits and leads so that the pipeline continues to flow. Pharmaceutical companies are experimenting with different types of partnering arrangements. Larger, more programmatic deals with academic institutes are typically focused on a specific therapeutic area. Other arrangements involve cherry-picking specific programs. Typically, these are further advanced, and the early data supports a strong chance of success.

The ability to move a lead compound farther down the pipeline may very well be the key to these academia/industry collaborations. During the early stages of drug discovery, researchers are still working to understand the fundamental biology surrounding a target. Frequently, a lead compound against a novel target is the key tool to validate that target and understand what indications or diseases it might be useful against. With data supporting the activity of lead compounds in specific disease models, identifying the most suitable drug company to partner with becomes more straightforward. As academic institutions can show more data, the model becomes more efficient.

By building high-throughput chemical compound screening facilities, academic institutions, with encouragement from the NIH, have helped bridge a notable gap in the drug pipeline. The next step is to redefine the relationships between academia and industry, a process that has already begun.

Ideally, industry and academia could combine their complementary skills to create the most robust possible drug pipeline. On the academic side, the basic science capabilities, combined with state-of-the-art screening facilities, will uncover disease pathways, exposing potential drug targets. Then academic institutions can screen compounds that impact those targets and hand off successful lead compounds to industry. Pharmaceutical companies would identify and acquire lead compounds that best fit their therapeutic focus and business plan. With their advanced in-house chemistry and pharmacology capabilities, they would then optimize these leads and take them through the rigorous process of preclinical and clinical trials. As this new model evolves, risk-sharing relationships between academic institutions that generate leads and outsourcing companies that specialize in medicinal chemistry and pharmacology are likely to develop, and projects will be advanced further along before these organizations begin partnering with pharmaceutical companies.

Ultimately, this appears to be a winning model for all participants. Academic institutions can move their research farther forward and learn more about the basic biology of disease. Industry can take more advanced lead compounds and shepherd them to clinical use. Hopefully, this will mean a robust drug pipeline and more therapeutic options for patients.

Michael R. Jackson, Ph.D., is vice president of drug discovery and development at the
Sanford-Burnham Medical Research Institute. Prior to joining Burnham, Jackson spent 15 years with Johnson & Johnson, where he served as senior vice president of U.S. drug discovery at J&J Pharmaceutical Research and Development (J&JPRD) and president of ALZA, a drug delivery company. He established J&JPRD's drug discovery research site in La Jolla, Calif., where he was most recently chief scientific officer. Jackson received his Ph.D. in biochemistry at the University of Dundee in Scotland and completed his post-doctoral training at The Scripps Research Institute (TSRI). He was a faculty member at TSRI before joining J&J.

The Scripps Research Institute (TSRI)

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