In 2022, the NHS spent £9.69 billion on prescribing drugs to patients in England. But ensuring these drugs are truly effective for patients remains a challenge for policy and health decision makers. In fact, 55% of adults are prescribed drugs that may be ineffective for them due to their genetic makeup.

Enter pharmacogenomics (PGx) research – a field that analyses the role of the genome in drug response. With a deeper understanding of the links between certain therapies and genes, PGx research can help achieve better outcomes for patients and save money that would otherwise be wasted on ineffective prescriptions.

Moreover, research from the U-PGx Consortium shows that altering drug or dosage according to a person’s genome could also reduce adverse drug reactions by 30%, which currently contribute to 6.5% of hospital admissions.

Read more: Wales to use pharmacogenomics in pharmacies by 2025

PGx support for drug decision-making is being trialled in many countries, including the UK. The NHS is currently pioneering PGx research through its genomic medicine service, with the goal of making Britain one of the first national health systems to offer whole genome sequencing as part of routine care. Thanks to recent advances in genomic sequencing technologies, this vision of PGx at scale is closer than ever to being realised.

 

The CYP2D6 gene

 

One example of PGx in action is the CYP2D6 gene, which directly influences the metabolism of around a fifth of the most prescribed medicines. Included in this group are opioids and selective serotonin reuptake inhibitor (SSRI) antidepressants, on which NHS England (NHSE) spent more than £412m in 2022.

Read more: Community pharmacists ‘critical’ to mainstreaming genomics, says geneticist

Depending on their CYP2D6 genetic variation, people may metabolise these medicines more slowly or rapidly. For example, 8% of the UK population lack the enzyme that reacts with opioids and SSRIs entirely; they metabolise the medicines so slowly that either they may never reach the therapeutic levels required for the drug to be effective, or conversely may increase their risk of overdose.

In contrast, 2% of the UK population have more than two copies of the gene, which causes ultrafast metabolism. Once again, this increases risk of overdose as drugs reach the bloodstream much faster and at a higher concentration. The key takeaway is that combined, 10% of people in the UK have a CYP2D6 mutation that severely impacts their ability to process these common drugs.

Read more: What role could pharmacies play in pharmacogenomic testing rollout?

If genetic screening was used to inform the prescribing of opioids and SSRIs, there is potential to save more than £41m per year. And this calculation only considers the extremes of the spectrum – it does not include the people with only a slightly reduced activity score.

Assuming similar PGx mechanisms were found for other drugs, PGx could deliver significant savings to NHS’s £9.69bn annual prescriptions budget in England.

 

What’s hampered PGx so far?

 

While many challenges have hindered widespread PGx implementation, limitations in sequencing technologies have, until recently, hampered PGx research and applicability to the broader population. This is because discovering new gene-drug relationships requires deep, highly accurate insight into the human genome powered by advanced sequencing.

While some genetic variation is straightforward to capture using technologies such as short-read genetic sequencing (where DNA is broken into small pieces for analysis), researchers cannot get the best-resolution answer using this technology when it comes to PGx.

This is because genes related to drug response are typically too complex and have variants that are too far apart to be captured by sequencing short segments of DNA.

Read more: What could a successful pharmacy pharmacogenomics service look like?

In the case of CYP2D6, the gene includes over 130 defined haplotypes known to impact drug metabolism, as well as a pseudogene that complicates analysis from short-reads.

This means incomplete coverage or mis-mapping of the genome may occur if researchers rely on short-read alone. As well as the accuracy issue, short-reads require running multiple assays and manually piecing together genomic data. This takes time and significant computational effort, which simply isn’t practical for patients who require swift treatment.

Long-read or “whole genome” sequencing offers an alternative method by sequencing full lengths of DNA that are kilobases long. Long reads successfully span large genomic regions and structural variants to afford researchers a deeper understanding of gene-drug relationships, with unbiased coverage to better capture variants present in all populations.

However, to date, long-read sequencing has had lower throughput and higher costs, making it more challenging to incorporate in large scale studies affordably.

 

Working towards making precision prescribing a reality

 

The good news is that developments in long-read sequencing have made the technology increasingly accessible. Overall, the cost of long-read sequencing has come down and throughput has increased.

A single whole genome sequencing machine can now deliver more than 1,300 human genomes per year, with reduced sample sizes, far fewer consumables, and exceptional accuracy. This means there’s less need to batch samples, which improves time-to-result. Labs will no longer have to choose between cost and turnaround speed, unlocking the possibility of the $1,000 genome with a 24-hour turnaround time.

Read more: ‘Super pharmacy’ CEO sets out plans for pharmacogenomics service

All these advances make it feasible to integrate long-read sequencing into PGx studies at scale. With the increasing pace of technological innovation, we can expect our understanding of the links between therapies and genes to expand rapidly over the coming years.

To secure a spot on the frontline of this innovation, healthcare, research, and government bodies must start investing in the latest, most sophisticated sequencing methods. Those that pioneer a path towards precision practices will ultimately be the first to start seeing the benefits of reduced wastage, and safer, more effective treatments.

 

Neil Ward is vice president of PacBIO EMEA