January 25, 2024 | In a big advance for precision medicine, researchers in Australia have developed a genetic biomarker of people’s response to sodium reduction. It is often but not always the case that modifying sodium levels lowers blood pressure by reducing the fluid volume of blood in the cardiovascular system, and knowing in advance how patients will respond could help eliminate the “treatment odyssey” that many of them are experiencing, according to Murray Cairns, Ph.D., professor at Hunter Medical Research Institute and the University of Newcastle (Australia).
The “pharmagenic enrichment score” (PES) under investigation represents a new and scalable diagnostic approach where the assessment of polygenic risk is constrained to the biology of a drug’s mechanism of action, explains Cairns. The focus is on the body’s sodium and potassium transport pathways in the case of hypertension, as was recently reported in a genetic interaction study published in Circulation (DOI: 10.1161/CIRCULATIONAHA.123.065394).
If clinicians had a means to match treatments to individuals, it would quickly eliminate one of the main dangers of the current trial-and-error approach—patients losing interest in trying to control their blood pressure at all. Treatment planning is complicated by the reality that three-fourths of hypertensive patients will need two or more drugs to move the needle and getting to that ideal combination takes time, he says.
It is currently estimated that about 70% of people have uncontrolled blood pressure and it contributes to one-fifth of all deaths from heart attack, stroke, kidney disease, and dementia, says Cairns. Blood pressure is easy to measure but even at deadly high levels people generally don’t feel any symptoms, which is why it is often referred to as the “silent killer.”
In Australia, roughly 30% of adults have hypertension, he adds. In the U.S., the figure is closer to 50%.
Hypertension, like most chronic diseases, has a “very significant genetic component,” continues Cairns. Most commonly these are single nucleotide polymorphisms (SNPs) scattered across the genome and thus are generally not considered to be clinically actionable. The sum of these effects is reflected in polygenetic risk scores, which are based on known disease associations.
Unfortunately, the scores aren’t particularly informative at the individual level because they are measuring the overall risk of developing chronic diseases that tend to be highly heterogenous. Whether the condition at hand is hypertension, type 2 diabetes, inflammatory disease, a psychiatric illness, or neurological disorder, the genetic component is distributed and “affects different systems and differentially in different people,” says Cairns.
In the latest study, investigators compared risk measurement with the biologically directed genetic scores to a standard genome-wide polygenic score for blood pressure. With the PES, both genetic risk and urinary electrolytes were found to independently correlate with blood pressure, but urinary sodium was associated with a larger blood pressure increase among individuals with the higher genetic risk in sodium- and potassium-related pathways. No strong evidence was found for an interaction between urinary sodium and disease-level scores.
The study leveraged data from approximately 300,000 genotyped individuals drawn from the UK Biobank cohort for whom blood pressure and urinary biomarkers of sodium and potassium intake had been measured. Urinary sodium levels served as a proxy of treatment with a sodium-lowering intervention.
Based on results of the study showing the gene-environment interaction, Cairns reports that he was just awarded a $2.6 million grant from Australia’s Genomics Health Futures Mission, to conduct an interventional clinical trial applying the PES method more broadly to different classes of antihypertensive drugs beyond those focused solely on sodium reduction. Researchers are working with several contract research organizations to ensure the investigator-initiated study will pass muster with regulatory agencies and the PES approach can be developed under the Software as a Medical Device (SaMD) framework. The protocol is expected to be registered on ClinicalTrials.com by the end of 2024.
At least 200 genotyped people are anticipated to enroll in the platform study where functional enrichment analysis will be done to sort the drugs according to their biological mechanism of action, he says. Outcomes from the genetically predicted medications will be compared to the standard of care, the bar being “more rapid and effective control of hypertension.”
The intellectual property for the technology and trial is owed by PolygenRx, the startup Cairns launched two years ago to commercialize the precision medicine platform for chronic diseases. He serves as CEO.
Cairns started his career in the pharma business with Johnson & Johnson but has been a professor of genetics for nearly two decades. He says he felt “compelled” by the potential of the PES-based platform to reconnect with his industry roots.
Since his background is in psychiatric genetics, the initial research focus was schizophrenia—an “extremely polygenic and heterogenous” psychiatric disorder that likely has thousands of genes impacting risk. “People present with symptoms of schizophrenia psychosis from a broad range of biological changes that affect the brain, so it is very difficult to treat people with anything other than an anti-psychotic drug.”
When the pandemic came along, Cairns and his team started looking at lung function and pneumonia because of the risk associated with COVID-19. Cardiovascular disease and risk factors like hypertension were among other obvious targets for the PES approach due to their significant impact on health and longevity.
The technology can be used for drug discovery and development, notably to de-risk clinical trials, says Cairns. When used as an inclusion criterion to identify drug responders, the model could potentially reduce the cost of studies dramatically. It may well serve as a companion or complementary SaMD diagnostic linked to a specific drug within its approved label or more broadly to a class of drugs.
In addition to recommending patients make lifestyle modifications, notably eating a heart-healthy diet with less salt, the standard frontline antihypertensive treatments include a diuretic along with an angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor, says Cairns. But multiple other drugs in the arsenal might get tried when patients have trouble meeting their blood pressure goal, among them calcium channel blockers, alpha blockers, and beta blockers that all directly impact the contractability of the heart as well as vasodilators that stop the muscles in the artery walls from tightening.
The pharmagenic enrichment scores are designed to guide clinician decision-making about which drug, or set of drugs, will work best for individual patients and is informed by the “effect size of the disease,” Cairns explains. PES uses components of global polygenic scores but focuses on specific biological pathways that can inform where drugs are going to have the most effect. “It has never been done before, and it’s a huge [untapped] opportunity”—and not just in the chronic disease space.
For almost any drug whose mode of action is known, and a genetic signal can be teased out, use of the PES model could be used to direct its use for treatment or even prevention, he says. In addition to chronic diseases, the model has been explored by Cairns and his team for drugs targeting cancer, pneumonia and acute respiratory syndrome, and rare diseases. The work extends to neurofibromatosis, a hereditary developmental condition, to look at variant signals indicative of disease severity so treatment can be more individualized.
As Cairns imagines it, future clinical care might begin at birth with a basic genome-wide SNP analysis that currently costs around $50. The information would be good for a lifetime and could ultimately be applied to potentially “thousands of conditions and thousands of drugs” to optimize treatment, he says.
That data might logically appear in a dashboard accessible to prescribing physicians in an electronic health record system, continues Cairns. The PES score for an individual would get benchmarked against the score for the population to provide an exact percentile and decile range of significance that can be quite stringent.
All kinds of novel and existing treatments may come up and potentially be deployed based on this guidance, he says. “There are probably thousands of endotypes in chronic disease that are potentially treatable in different ways.”
So, in addition to becoming broadly used in the clinic, the PES framework could identify opportunities for treating new phenotypes of disease in different ways, says Cairns. Sponsors may also wish to employ the model in their selection process for trial participants for drugs exhibiting mixed results preclinically or in phase 1 trials. As it stands, only one out of 10 drugs entering human testing end up being successful through phase 3 trials.
A major challenge in conducting a clinical trial for a chronic disease is that a comparison typically needs to be made against the standard of care, he says, which makes studies many times larger and longer than for rare and orphan diseases where there is often no generally accepted treatment to outperform. Investment partners are consequently harder to find without compelling evidence that it is a financial risk worth taking—in this case, by better selecting recruitment targets to improve the odds of study success.
From a societal standpoint, chronic diseases simply can’t be ignored, says Cairns. According to the National Council on Aging, nearly 95% of adults 60 and older have at least one chronic condition, while nearly 80% have two or more. It is more often the reason they die than old age.
Among people with hypertension, a much larger proportion of people suffer from disease-related disabilities than succumb to it. The current estimate by the Pan American Health Organization is that by 2030, the financial burden of caring for people with non-communicable diseases—notably, cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes—will mushroom to nearly $30 trillion globally.
“It is important to consider that chronic disease has a significant genetic component, and it is potentially clinically actionable,” emphasizes Cairns. Using genetics to inform treatment for hypertension and improve patient outcomes would be good news for afflicted individuals as well as society given that it is such an expensive and devastating condition. In Australia alone, reducing the prevalence of hypertension by even 25% could save the government $34 billion per year, he notes.