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PolygenRx Wants to Use Genetics to Guide Chronic Disease Treatments, Starting With Hypertension

Double-stranded DNA with mutation in a gene, conceptual illustration

NEW YORK – Genetics, often typecast as the future of medicine for rare and monogenic conditions, could also be used to guide treatments for chronic diseases affecting millions of people.

At least, that's the vision behind PolygenRx, a startup cofounded by two Australian researchers, Murray Cairns, a professor at the University of Newcastle's biomedical sciences and pharmacy school, and William Reay, a statistical genetics research fellow at the University of Tasmania's Menzies Institute for Medical Research.

"We have a massive problem with chronic disease, globally," said Cairns, who studies the molecular biology of common multifactorial conditions and now serves as PolygenRx's CEO.

There are numerous conditions that fall under the umbrella of chronic diseases and require ongoing medical treatment, including some of the leading causes of mortality, like heart disease and diabetes. In the US, for example, more than half of adults have at least one chronic disease, and about 40 percent of Americans have multiple.

These conditions aren't typically thought of as driven by genetics, but variations in many genes, cumulatively, can often affect how these diseases manifest in individuals.

"Different people can present with the same disease, but have quite a different genomic profile," Cairns said.

PolygenRx, founded in 2021 in Newcastle, Australia, is building a platform to analyze and identify genetic variants related to chronic diseases and study how, based on those genes' functions, that can potentially inform treatments. The company uses this platform to identify genetic variants that are related to biological pathways and are likely to be able to be modulated by drugs and to generate a "pharmagenic enrichment score."

As a new company, PolygenRx is hoping its platform will attract drugmakers and contract research organizations (CROs) that want to identify biomarkers relevant to therapies they're developing. Within these partnerships, PolygenRx would identify biomarkers that distinguish best responders to treatments, so that organizations can enrich drug trials with these populations, Cairns said.

While there are many potentially promising drugs in development, few ultimately reach the market. In fact, nine out of 10 investigational drugs fail clinical trials. That's in part because people respond to the same drugs in different ways, Cairns noted, which is a particular concern in patients with chronic diseases for which there may be many underlying causes.

As such, "it's difficult to find a drug that fits the problem in every case," Cairns said. 

For example, nearly half of the adults in the US have hypertension, according to the Centers for Disease Control and Prevention. But hypertension doesn't have a single cause and can be linked to numerous factors, including genetics, aging, and lifestyle.

In an observational study Cairns coauthored and published in Circulation last year, researchers sought to establish evidence that a polygenic risk score could identify hypertensive patients who would respond best to blood pressure treatments that specifically lower sodium. To do this, they analyzed data from nearly 300,000 UK Biobank participants and assessed whether there was an interaction between biomarkers for sodium and potassium intake in urinary electrolytes, blood pressure, and a polygenic risk score related to pathways of sodium and potassium transport. They found that higher presence of urinary sodium was linked with higher blood pressure among those with higher genetic risk, which they said suggests patients with those risk scores would likely benefit from sodium-lowering medications or dietary interventions.

The pharmagenic enrichment score used in the research paper incorporated 487 genes associated with nutrient absorption, transport, and renal excretion related to sodium and potassium, including, for example, SCNN1A, which is involved in sodium transport, and KCNA1, which is involved in potassium transport.

The firm is also looking to develop clinical decision-support software to guide prescriptions of certain drugs, including for hypertension medications. This type of tool would require clearance from regulators, and PolygenRx initially plans to seek approval from the Food and Drug Administration for this software as a Class III medical device as well as from Australia's Therapeutic Goods Administration. Cairns said PolygenRx expects to have clinical evidence to support such applications by the end of 2025.

A third and long-term ambition for PolygenRx is to develop its own drugs by licensing promising assets that failed previous studies but that could be rescued in biomarker-targeted groups. "But that obviously requires either partners that want to engage in those projects or investment from venture capital or other [organizations]," Cairns said.

So far, the company has signed a handful of agreements with CROs and drugmakers, and last year announced it had inked an agreement with Atherion Bioresearch, a CRO. Cairns said the company's primary goal currently is building evidence on its platform. He declined to disclose how many customers the company has signed.

The company is still at an early stage, Cairns said, with just seven employees, including data science and genomics researchers as well as a small business development team. While the company has about A$7 million (US$4.7 million) to put toward two clinical trials this year, it is also considering financing options in late 2024 or early 2025 to raise funds for the business.

"Part of our strategy was to have this [platform] strongly anchored in the science. … We want to use that as a marketing tool as well," Cairns explained.

PolygenRx is working toward launching an interventional clinical trial in hypertension later this year, in which investigators will identify best-fit treatments for patients guided by the company's genetic analysis and compare that against standard care.

Hypertension treatment can include just lifestyle modifications, or lifestyle changes paired with taking one or multiple blood pressure medications, said Aaron Sverdlov, a professor in cardiology at the University of Newcastle and coinvestigator on the planned clinical trial. These drugs have different mechanisms: For example, medications might include diuretics that lower sodium, vasodilators that prevent the veins and arteries from narrowing, and ACE inhibitors that relax blood vessels.

"There is a wide range of effective medications for hypertension acting through a variety of mechanisms," he said. "How each individual patient will respond to a particular medication both in terms of effectiveness and also in terms of tolerability is nearly impossible to predict without trying the medication first."

The study PolygenRx is planning will provide evidence on whether genetic insights can cut down the time it takes to get a patient on an effective treatment and whether that genetically informed care improves the patient's outcomes compared to standard care.

Through partnerships with multiple types of organizations, Cairns said he hopes that a tool like PolygenRx's platform can get patients on treatments they will benefit from most. "If we understand that genetic component, we have a huge advantage in potentially directing treatment," he said.