Layton Harris Smith Ph.D. Director, Drug Discovery and Pharmacology Sanford Burnham Prebys Medical Discovery Institute
Bridging Drug Discovery’s Valley of Death Is a Good First Step
We need more new drugs to treat more diseases. We need them faster. We need them to work better. We need them to cost less. Yet, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), for every 5,000 potential new drugs tested, only five make it to clinical trials, and only one is ever approved for use in humans.
Why? While there are certainly financial and regulatory challenges to drug discovery and development, the primary reason for failure is not financial (pharma spends more than $50 billion annually on R&D) or regulatory (FDA had a 77% approval rate in 2014).
The real reason we don’t have as many new drugs as we’d like is because, more often than not, they just don’t work as expected once we test them in humans. In many ways this high failure can be blamed on the fact that we lack innovation in the earliest stages of drug discovery, and that’s largely due to a big gap in the drug development pipeline known as the “Valley of Death.”
What we mean is this: scientists around the world toil in universities and research institutes, conducting basic research experiments to determine how cells work, what happens when they grow out of control, and when they die prematurely. Sometimes they find potential new drug targets. These are usually genes that, when removed, stop tumors from forming or protect neurons from degenerating in Alzheimer’s disease—at least in cells growing in a laboratory dish, or at best, in a mouse. They publish their results, and that’s traditionally where academia’s contribution to the drug pipeline ends.
There’s no question that this is critical work that has increased our understanding of human biology and how it goes awry in disease. But very rarely does basic research lead to directly to a therapy that helps a patient.
Meanwhile, at the other end of the drug pipeline, pharmaceutical industry researchers are investigating the pharmacology and toxicology of chemical compounds—not genes—that cure or modify disease. They are looking for novel chemical compounds (potential drug precursors) that have at least proved effective and safe in animal models and passed a few other measures of successful drug development, before investing the billions of dollars needed to bring a new therapy to market.
Valley of Death
Do you see the disconnect? Genetic manipulation is a powerful approach to understanding basic biology, but it’s not a feasible means of treating disease. Pharmaceutical researchers understand that chemical compounds are the most effective and cheapest method for doing so.
The Valley of Death that separates these two ends of the drug discovery spectrum is not only wide, but there is little capability for either side to bridge it.
On one side of the valley, few academic scientists have the expertise and resources to take their work through the next steps necessary to actually treat those diseases in humans—validating the molecular targets they’ve identified as contributing to disease pathology and screening diverse libraries of chemical compounds for their abilities to inhibit or boost the activity of those targets.
On the other side stands the pharmaceutical companies, hesitant to gamble billions of dollars on initial findings that may not translate into humans at all.
Yes, part of the problem is that the low hanging fruit has already been picked. But it’s as if both sides are waiting for someone else to find a way to reach for the next best options.
Academia Bridges the Valley
There is a way to bridge drug discovery’s Valley of Death. Not just in theory, but already in practice. A few universities and nonprofit research institutions have created academic drug discovery and development centers that can translate basic research findings into potential clinical products. These on-campus facilities are fully staffed with experts (often pharma industry ex-pats) in medicinal chemistry, pharmacology, high-throughput screening, drug metabolism, bioinformatics, and more. They are armed with leading-edge, automated equipment rarely found outside pharmaceutical companies.
But there are surprisingly few of these engines of therapeutic innovation. While about one hundred academic institutions are dipping their toes in the water, there are only about six academic facilities in the nation that could realistically produce a product a pharmaceutical company might take interest in.
These academic drug discovery and development facilities have opened the doors of their state-of-the-art infrastructure to partner with disease experts, academic researchers and clinicians who are very good at what they do and have great ideas, but who lack drug discovery expertise or training.
Then, these innovative drug discovery teams seek to partner with pharmaceutical companies for early-stage funding and assistance as they move potential new drugs along the pipeline to the far side of the Valley of Death.
In this model, academia and industry meet in the middle of the Valley of Death. Here, they share in the risks, and the rewards.
Government plays a role in bridging the Valley of Death, too. The state of Florida has jumped in with both feet with the Florida Translational Research Program (FTRP), a unique mechanism for drug discovery collaboration and funding. FTRP funding has been tremendously successful in drawing in academic researchers, who in the past three years have submitted more than 97 new ideas to Sanford Burnham Prebys. These ideas have led to 48 screens (tests of thousands of chemicals against a biological target), 15 lead compounds (possible precursors to new drugs), and five patents for new chemical entities with potential utility as new medicines.
These are all promising ideas that would otherwise simply have languished on library shelves. But thanks in part to FTRP, we have been able to turn these ideas into the tools that pharmaceutical companies need to take things to the next level.
Layton Harris Smith, Ph.D. ([email protected]), is director, drug discovery and pharmacology at Sanford Burnham Prebys Medical Discovery Institute at Lake Nona.