A study published Sept. 7, 2020, in Nature Medicine, reports identifying a “polygenic risk score” that shows when a drug, be it an approved medication or an experimental one, poses a risk of drug-induced liver injury (DILI).
The work was conducted by consortium of scientists from Cincinnati Children’s in collaboration with experts from Yokohama City University, the T-CiRA Joint Program, Takeda Pharmaceutical Company, and the Tokyo Medical and Dental University in Japan; Nottingham and Newcastle Universities in the United Kingdom; the Icahn School of Medicine at Mount Sinai in New York, and the University of North Carolina, The findings take a large step toward solving a problem that has frustrated drug developers for years.
"So far we have had no reliable way of determining in advance whether a medication that usually works well in most people might cause liver injury among a few," says Jorge Bezerra, , Director, Division of Gastroenterology, Hepatology, and Nutrition at Cincinnati Children’s. "That has caused a number of promising medications to fail during clinical trials, and in rare cases, also can cause serious injury from approved medications. If we could predict which individuals would be most at-risk, we could prescribe more medications with more confidence."
Now that reliable test might be just around the corner. "People could take the genetic test and know their risk of developing DILI," says corresponding author Takanori Takebe, an organoid expert at Cincinnati Children’s who has been studying ways to grow liver 'buds' for large-scale use in research.
The team developed the risk score by re-analyzing hundreds of genome-wide association studies (GWAS) that had identified a long list of gene variants that might indicate a likelihood of a poor reaction in the liver to various compounds. By combining the data and applying several mathematical weighting methods, the team found a formula that appears to work.
- The risk score takes more than 20,000 gene variants into account.
- The team confirmed the score’s prediction power in cell culture, in organoid tissue and by using patient genomic data already on file.
- The score was valid in tests involving more than a dozen medications: cyclosporine, bosentan, troglitazone, diclofenac, flutamide, ketoconazole, carbamazepine, amoxicillin–clavulanate, methapyrilene. tacrine, acetaminophen, and tolcapone.
- The test works for different types of drugs because the score focuses on a set of common mechanisms involved in how the liver metabolizes a drug, including oxidant stress pathways in liver cells and endoplasmic reticulum (ER) stress—a disruption of cell function that happens when proteins cannot fold properly.
How can a risk score help?
For clinicians, this would allow them to run a quick genetic test to identify patients at higher risk of liver injury before prescribing medications. The results might prompt a doctor to change the dosage, order more frequent follow-up tests to catch early signs of liver damage, or switch medications entirely.
For drug research, the test could help exclude people of high risk of liver injury from a clinical trial so that the benefits of a medication can be more accurately assessed.
Liver toxicity has caused a number of drug failures over the years. Takebe says both patients and the drug maker were disappointed when a potential diabetes treatment called fasigliam was withdrawn in 2014 during phase 3 clinical trials. Some of the participants (at a rate equivalent to about 1 in 10,000) experienced elevated enzyme levels that suggested potential liver injury.
"This is the most significant breakthrough that would transform liver safety in drug development," Prof Guruprasad Aithal, Professor of Hepatology, University of Nottingham and the Deputy Director of NHIR Nottingham BRC, one of the authors of this paper said. "Interestingly, discovery from patient-based research was applied to the cell-cultures in the laboratory to find an innovative solution to an obdurate problem which animal models couldn’t resolve."
While such risks may appear low, at the time there was no way to predict which people would develop DILI, making the drug unacceptably dangerous. But the new polygenic risk score would make it possible to produce liver organoids that exhibit key risk variants to determine if a drug is harmful before people ever take it.