Bridging the Pharmaceutical "Valley of Death"
In the world of drug discovery, there is a place that haunts everybody - from basic researchers to needing patients - known as the "Valley of Death”. The Valley of Death is where the vast majority of new therapeutic ideas go to die.
The Valley lies between two enormous mountains. The first mountain is called "Basic Science. The other mountain, across the Valley of Death, is occupied by the pharmaceutical industry including "Big Pharma”. To a large extent, the inhabitants of Basic Science and Big Pharma speak different languages.
In many regards, they live in completely different worlds. The inhabitants of Basic Science only have a rudimentary understanding of the drug development process. In general, for instance, Basic Scientists have little detailed knowledge of the desirable characteristics of drugs. Including, for instance, ADME (absorption, distribution, metabolism, elimination), pharmacokinetics, pharmacodynamics and the requirements for an IND (Investigational New Drug) application. Yet, they have exquisitely detailed knowledge of molecules, their interactions, and their potential role in disease states. Some of these molecules may indeed turn into viable drugs, but many more promising ones die in the transit across the Valley.
From the other side of the Valley, Pharma requires many boxes to check before they can commit resources to ideas emerging from the Basic Sciences for drug development. Over the past decade, Big Pharma has chosen to commit relatively fewer resources to internal research and development (R & D). Big Pharma has "Basic Science". It has become more reliant on Basic Science leads. The shift away from R & D has pushed the requirements for program take-up by Pharma towards more finished products. Typically, those that have already passed through proof of concept (usually phase 2 human clinical trials). Funding for such programs is in short supply in Basic Science circles. The limited opportunities via NIH or other national funding agencies. Many promising Basic Science ideas never advance far enough through preclinical or early-stage clinical work to have a low enough risk profile for Pharma to develop them further.
Another factor is that Basic Science (particularly in Academia) moves at a snails pace. With long funding cycles, slow review processes (compared to those in Pharma), and high rates of rejection from national funding agencies such as NIH. Publication of results is a critical aspect of Academia and a prerequisite for funding. Basic Scientists then tend to publish early compared to Pharma and thus, from a intellectual property perspective, begin the patent life clock ticking. So many projects languish for long periods in the intellectual property banks of large universities and do not advance sufficiently to become interesting to Pharma. Their patent lives are too short to make returns from commercialization possible. If Basic Scientists are able to advance projects using NIH or similar funding capabilities, the development time is likely to be much longer than it would be in a Pharma setting.
Finally, there may be other challenges for the advancement of early-stage drugs from Basic Science. Such as the tendency of Academic centers being siloed - with distinct departments such as medicinal, chemistry, and biology. Pharma, and particularly the larger biotech companies, have resources which stretch across many disciplines and tend to be more integrated and able to flow early-stage drugs from one area to another. But, even large Pharma may suffer from siloed thinking with a lack of integration across disciplines.
At the Roskamp Institute, we try to breach some aspects of the Valley of Death in the very early stages of a drug discovery program. For instance, very early in our exploration of molecular pathways in a disease we ask ourselves: "How “druggable” are the molecules in the pathway?" Furthermore, the decision to nominate a molecule as a potential drug requires the consideration of many factors. Some of which were mentioned above (ADME, pharmacokinetics, pharmacodynamics et cetera) and so the integration of drug development knowledge across disciplines is critical. In subsequent articles, we will explore different approaches to overcoming the Valley of Death from both sides.
