Genomics

The pharma industry needs a way to ensure the right therapies are getting to the right patients, in a timely and cost-effective way. How are advances in researchers’ understanding of genomics aiding not only precision medicine for rare diseases, but also for common health conditions?

Peter Donnelly at Genomics

For too long, we have lived in a world where billions are spent on clinical trials that ultimately fail, and where patients receive treatments that simply don’t work for them. That can now change.

Its long been known that genetics is an important factor for rare diseases and cancer. Today, it is understood to be a significant factor for all major chronic diseases as well. Given this, genetic information is critical in the development of precision medicine – getting the right treatment, prevention, or screening to the right people at the right time.

The benefits of using genomics to develop effective and accurate treatments are game-changing for the life sciences industry. It is now well-established that the use of human genetics can address the pharmaceutical industry’s greatest challenges: identifying novel drug targets for first-in-class and best-in-class products. Targets with human genetic support are more than twice as likely to succeed in clinical trials.1 Genetic risk technology can identify patient populations that are most likely to benefit from a particular therapeutic, leading to more precise and successful clinical trials and the maximisation of current portfolios through indication expansion.

For life sciences organisations, the power of genomics is rapidly changing the way the industry approaches drug discovery and development (DD&D).

The role of genetics in addressing common chronic diseases

Until a few years ago, if researchers had the entire DNA sequence of a healthy person in early middle age, you would learn something medically actionable in only 1-2% of cases.2 That position has recently changed dramatically. Even considering a restricted set of seven to ten common diseases, the use of genomic information allows researchers to learn something medically actionable in a quarter of all cases, and this fraction will only grow as additional common diseases are surveyed. 3,4

Genetics has traditionally played into healthcare via what is called genomic medicine, in which a single genetic change has major health consequences. Examples of these conditions include cystic fibrosis, Huntington’s Disease and muscular dystrophy. The UK is a world leader in this area through the 100,000 Genomes project (Genomics England) and the Genomic Medicine service within the NHS. 5,6 These conditions are often very serious, but thankfully, they are both individually and collectively rare. Many of them manifest early in life, so for a healthy middle-aged person, there are unlikely to be any single genetic changes of major impact to be discovered in their DNA.

In addition to these rare conditions, genetics turns out to be fundamentally important for all the common diseases as well – diseases like heart disease, diabetes, breast and prostate cancer – the conditions which cause most of the sickness and premature mortality in our populations, and which use 70-80% of healthcare budgets.7

It is only in the last few years that researchers have learnt how to measure and quantify the genetic component of risk for each of the common diseases. It is now known that for each disease, there are a million or more places in our DNA that affect our chance of developing the disease.8 This can be summarised for each disease by what is called a polygenic risk score (PRS), with a single genetic test taken once in a person’s life, revealing their risk scores for all the common diseases. This approach is called genomic prevention.

The impact of genetics is large. For example, some people are 20 times more likely than others to develop type 2 diabetes.9 In coronary artery disease (CAD), identification of individuals at highest risk – ideally before onset – remains a significant public health need. Recent studies have shown that using PRS can identify an additional 20% of the population with a three-fold increased risk of CAD, and identified 3% of healthy individuals with a risk of future CAD events equivalent to the recurrent event risk in those with existing disease. 10 In breast cancer, identifying and screening women according to their PRS could improve prevention strategies.

A recent study has shown that the lifetime risk of overall breast cancer in the women with the highest genetic risk was 32.6%. 11 Those in the top 1% of genetic risk were 11 times more likely to develop breast cancer than those in the lowest 1% of risk – 33% versus 3%. 11 In prostate cancer, there are 15-fold differences. 12

Obesity also has a major genetic component. In young adults, those with unhelpful genetics are 12 times more likely to transition to obesity in middle age than those with helpful genetics. 13

This presents a totally different and new opportunity. Each of us will be at high risk for a few diseases because of our genetics, but neither we – nor our doctors – will know which. But with genomic prevention, researchers can now measure and understand those risks when a person is still healthy, years before any symptoms develop. That allows health staff to give advice to at-risk individuals about the particular steps they can take to help them live a longer, healthier life. But critically, the information will allow health systems to target all of their current screening and prevention programmes more effectively – we can get the right people into the right programmes at the right time to help avoid disease entirely, or to catch it early when outcomes are best. Getting prevention right through the use of powerful personalised risk estimates could be a game-changer.

There is emerging science for several diseases, which indicates those at higher genetic risk of disease are those most likely to respond to pharmaceutical interventions. An exciting new opportunity is, therefore, arising, where genetic risk scores can be used to identify those who are most likely to benefit from a particular treatment.

Genomics supercharging precision in DD&D

Genetics provides a powerful route to the discovery of novel drug targets for diseases with serious unmet need, with clear evidence showing that targets with human genetics support are more than twice as likely to succeed in clinical trials. 14 Genetic information, combined with advanced statistical analysis powered by artificial intelligence and machine learning, provides critical insights into genetic variation, and the causes and consequences of human disease. This supports rapid and effective decision-making across all therapeutic areas, fundamentally enhancing drug R&D and the development of targeted personalised treatments. This also helps companies to maximise the potential of current product portfolios, through indication expansions for existing therapeutics.

Genetic risk technology also empowers pharmaceutical companies to assess individual genetic risks and design safer, de-risked clinical trials, ensuring higher success rates and improved patient safety. Powerful use of genetics, often combined with other ‘omics, supports more robust trial designs and advances in innovation in DD&D. By supercharging efforts in DD&D with genomics, companies are more likely to develop first-in-class and best-in-class medicines, meeting significant unmet health needs.

Unlocking the potential of precision medicine of the future

Using genomics has the potential to increase the success of clinical trials, increase patient safety, develop new treatments for diseases with significant unmet need and ensure patients receive treatments that work for them. With advances in the field, using genetic information in life sciences will be a central part of a future of successful, powerful, personalised medicine.

References:
1. Minikel E et al (2024), ‘Refining the impact of genetic evidence on clinical success’, Nature, 629(8012), 624-629

2. Van Hout C V et al (2020), ‘Exome sequencing and characterization of 49,960 individuals in the UK Biobank’, Nature, 586, 749-756

3. Lennon N J et al (2024), ‘Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations’, Nature Medicine, 30(2), 480-487

4. Chuong M et al (2024), ‘Preventing premature deaths through polygenic risk scores’, MedRxiv

5. Visit: genomicsengland.co.uk/initiatives/100000-genomes-project

6. Visit: england.nhs.uk/genomics/nhs-genomic-medservice/

7. Visit: england.nhs.uk/wp-content/uploads/2013/07/nhs-belongs.pdf

8. Visit: nature.com/articles/s41586-024-07316-0

9. KheraAVet al (2018), ‘Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations’, Nature genetics, 50(9), 1219-1224

10. Patel A P et al (2023), ‘A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease’, Nat Med, 29, 1793-1803

11. Mavaddat N et al (2019), ‘Polygenic risk scores for prediction of breast cancer and breast cancer subtypes’, The American Journal of Human Genetics, 104(1), 21-34

12. Conti D V et al (2021), ‘Trans-ancestry genomewide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction’, Nature Genetics, 53(1), 65-75

13. Khera Amit V et al (2019), ‘Polygenic prediction of weight and obesity trajectories from birth to adulthood’, Cell, 177(3), 587-596

14. Visit: journals.plos.org/plosone/article?id=10.1371/ journal.pone.0307270#abstract0

Professor Sir Peter Donnelly FRS FMedSci HonFIA, is the CEO and founder of Genomics. He has been a world leader in human genetics for over 20 years. Peter was one of the main players in what has been called the ‘Genetic Revolution’, the transformation in our knowledge of how genetics plays into all the common diseases, like heart disease, diabetes and cancer. He held leadership roles in many of the major international and national human genetics studies of this century, including the HapMap Project (the successor to the Human Genome Project) and the Wellcome Trust Case Control Consortium.