Why genetics makes drug development more reliable – and more human

Developing new drugs is not for the faint-hearted.

“It’s a pretty perilous journey,” says Paul Nioi, vice-president of discovery and translational research at Alnylam Pharmaceuticals. “It’s expensive and time-consuming, and less than one in ten drug candidates wins approval, a proportion that has barely budged in decades.”

Most drug programmes fail because the candidates have little to no effect once tested in humans. Traditionally, targets are selected based on experiments in animal models or using in vitro cell cultures. These models may not translate.

Some pharmaceutical companies are using a more human-focused method of finding targets: looking for changes in the human genome linked to diseases. Genetic validation can improve the odds in drug development, says Matthew Nelson, head of genetics at biomedical investment company, Deerfield. “It’s the only source of evidence that gets at the root cause of disease,” Nelson says.

Drug researchers measure many biological factors, from protein levels to epigenetic changes, to understand a noncommunicable disease. But it’s often impossible to determine cause and effect: whether the disease process is changing the levels of these biological factors, or whether the factors are having some influence on the disease process itself.

Tracing the pathway from genetic variant to drug target in people with a disease allows scientists to be sure they’re targeting the underlying drivers of disease, rather than symptoms.

In 2015 Nelson demonstrated¹ that drug mechanisms with supporting genetic evidence were twice as likely to work in the clinic. In 2023, he and his colleagues repeated the analysis with new genetic data, and found the effect was even larger — in a preprint, they estimate the probability of success with genetic evidence is 2.6 times greater².

The genetic advantage in drug development is clear, so what are the technologies driving this revolution in the making, and what does the future hold?

A genetic revolution

The Human Genome Project laid the foundation for genetic medicine by generating the first sequence of the human genome in 2003. In the two decades since then, faster and more affordable next-generation sequencing has helped scientists read countless more genomes, many of which are stored in data repositories like the UK Biobank.

The UK Biobank includes data from 500,000 volunteers. In addition to their complete genomes, the database includes lifestyle information, physical measurements and biological samples. Profiles are linked to medical records so individuals can be followed over time to study the causes, progression and treatment of disease. More than 30,000 researchers regularly use the data, says Naomi Allen, the biobank’s chief scientist.

Having access to genetic data and records from such a large group has been a game-changer for researchers, Allen says. Rather than spending months on genome-wide association studies, they can access that data at the touch of a button.

“Something that used to take three months, you can do in an afternoon,” she says. “It transformed the way researchers viewed the genetic determinants of disease.”

Targeting genes with RNAi

The UK Biobank is still expanding. Alnylam and seven other pharmaceutical companies helped sequence the exomes of most of the biobank’s 500,000 participants, releasing the data in July 2022. As exomes are the parts of the genome that encode information for protein synthesis, these more-granular data help researchers identify drug targets faster, says Allen.

“It’s the perfect playground for pharmaceutical companies to identify potential targets because of their known association with variants of interest,” she says.

Whereas many pharmaceutical companies look for genetic variants that cause disease, Alnylam — a pioneer in therapies based on RNA interference (RNAi) — takes a different approach, says Nioi. The company looks for people who have won the ‘genetic lottery’, who carry genetic mutations that protect them from developing a disease. The idea is then to ‘silence’ those genes using RNAi to recreate the genetic mutation in others — hopefully providing the same protection.

The strategy has been fruitful: Alnylam has four RNAi therapeutics approved in the United States and a busy pipeline in clinical development. “Our focus on genetic validation has helped our drug candidates achieve a clinical trial success rate that’s six times the industry average,” says Nioi.

Alnylam has already identified promising targets using the UK Biobank’s data. In 2022, the company found that people with a loss-of-function mutation in the INHBE gene had less abdominal fat and a healthier waist-to-hip ratio³. The mutation was associated with lower blood pressure, LDL cholesterol and triglycerides, and lower risk of cardiovascular disease and type 2 diabetes. Alnylam suspects silencing the gene in others may provide similar benefits. INHBE is in the company’s sweet spot, says Nioi. Currently in the preclinical stage, it’s a protective knockout only expressed in the liver, the organ easiest to target with RNAi.

Further expansion

The UK Biobank is facilitating important discoveries, but its size is a limiting factor, says Nelson. “500,000 sounds like a lot, but if you want to study something that has a 0.1% population frequency, you’re going to need biobanks with tens of millions of people,” he says.

So Alnylam is seeking other genetic treasure troves. The company has joined a large sequencing effort called Our Future Health, a collaboration between the UK government, the UK National Health Sevice and industry. This initiative aims to recruit five million participants, with more than 800,000 already consenting.

To help address the lack of ethnic diversity in the biobanking data set, Alnylam has also partnered with the Discover Me South Africa study, which is set to enrol up to 100,000 people in Durban, South Africa, who will share health and genetic information for research purposes.

Even as the biobanking world expands, sequencing is not yet commonplace in routine health care. Eventually, Nelson says, all of us will be sequenced, and sequence data will guide health-care decisions. If that data can also be used for research, biobanks could jump from a few million sequences to tens or hundreds of millions.

“We’re very far from peak genetics,” says Nelson. “Sometime in the next decade or so we’re going to see another huge uptick.”

Fully integrating genetics into the drug development process will take the combined efforts of many partners for years to come. But the process has begun, and pioneers like Alnylam have already taken the first steps.

“Across our clinical pipeline and our approved medicines, there isn’t a single example where we don’t have human genetic evidence to give us confidence we are targeting something important in the disease process,” Nioi says. “That’s the foundation of everything we do.”