Nature’s gift to medicines discovery

Human genetics is transforming the way new drugs are discovered, giving unprecedented hope for delivering better medicines

Nadeem Sarwar is president of the Eisai Andover innovative Medicines (AiM) Institute. Located in the greater Boston biotech hub, AiM is a medicines discovery innovation unit of 90 integrated scientists at a dedicated research facility exclusively focused on delivering novel, targeted medicines from human genetics. To learn more about the Eisai Aim Institute, please click here.

Making medicines is tough. Coming up with a new idea about how to treat or (even better) prevent disease, then turning that idea into an effective and safe medicine can take a long time and a lot of money.

According to a recent analysis by the Tufts Center for the Study of Drug Development, the average time to develop a drug has now risen to 12 years, with an average cost of $2.6 billion for each new medicine that makes it to patients. The primary reason it takes so long and costs so much? The number of very expensive shots on goal that are taken before a new, effective and safe medicine is identified. It is estimated around 80 percent of new drug discovery programs don’t even make it into human clinical trials - and of those that do, less than one in two go on to become medicines.

In a world where the demand for effective new medicines has never been greater, such attrition and delay is unsustainable. We need a new paradigm for making new medicines. In particular, we need a much faster way to pick-out the needle of good idea from the haystack of bad ones, so resources and efforts can be focused on those few ideas that have the greatest likelihood of becoming effective new medicines that can meet patient’s needs.

Traditionally, the source for many new ideas for medicines has been mice. News headlines frequently proclaim “Disease X cured by scientists!” (only for the fine print to state “disease X” was in mice, and “cured” was in the eye of the beholder). Not entirely surprisingly, the causes and determinants of disease in mice are quite different to those in humans. This “lack of translation” of ideas that were effective treatments in animal studies but proved to be unsuccessful in humans, has been a major source of frustration and failure in drug discovery over the past several decades.

The solution – it turns out – may reside within each of us. Over the past few years, huge advances have been made in our ability to study how our genetic make-up impacts health and disease. We have developed a better understanding of the human genome and made several rapid technological advances, so we are now able to study how genetic variation between people is associated with the risk of disease (as well as with progression of disease). Such genetic associations provide clues about mechanisms that could be targeted by drugs to treat, prevent or delay disease.

The key difference is that the source of the clues is now humans, not mice. Indeed, several analyses have demonstrated that drug targets supported by human genetic data are about twice as likely to become successful medicines as drug targets that are not. This doubling in the odds of success provides a new paradigm for drug discovery and development, and one that has given medicine makers from across sectors reason for cautious optimism.

Huge investments are being made across public and private sectors to harness the potential human genetics provide to disrupt the way drug discovery is conducted, with the ultimate aim of increasing the success rate of delivering effective new medicines to patients. The All of Us Precision Medicine Initiative, for example, will generate and collate genetic and other data on one million people to provide a detailed data resource for scientists to mine and identify genetic clues for new drug targets.

Within the pharmaceutical industry, dedicated drug discovery innovation units are being established to focus on realizing human genetic guided drug discovery. Traditional boundaries that have tended to silo research being conducted in different sectors are being broken, with creation of several “public-private partnerships” that bring together multi-disciplinary scientists from across industry, academia and government to accelerate human genetic guided drug discovery.       

The poster child for this new approach to drug discovery, and one that is already helping patients, is a new treatment for high cholesterol levels that inhibits an enzyme called PCSK9. In 2006, researchers at University Texas South Western discovered a mutation in the PCSK9 gene, which stops the body from producing the PCSK9 enzyme. Scientists learned that people who inherited this mutation had very low levels of bad cholesterol and, consequently, a substantially reduced risk of developing heart disease. This discovery led to the idea that, if inhibition of PCSK9 by an inherited genetic mutation leads to lower levels of cholesterol and of heart disease, perhaps inhibition of PCSK9 by a drug would do the same. Fast forward a few years, and that’s exactly what scientists have been able to demonstrate. Two PCSK9 inhibitors are now FDA-approved as adjunctive therapy in a subset of adult patients with the high unmet medical need for cholesterol control.[i]   

The approach exemplified by PCSK9 is now being employed across multiple therapeutic areas, including heart disease, diabetes, Alzheimer’s disease and autoimmune diseases.

The need for effective new medicines across a range of diseases is considerable, as the global population continues to grow and age. Human genetics provides a new source for the discovery and development of such medicines, with high hopes that this new approach will lead to better, faster treatments for patients.


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