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Spheres of influence

Genentech and AstraZeneca team up on preclinical liver toxicity

AstraZeneca plc and Genentech Inc. have joined forces to test whether a liver spheroid system can improve upon the gold standard for preclinical prediction of hepatotoxicity. The goal is to raise the bar on preventing compounds from reaching the clinic that end up causing drug-induced liver injury -- a major source of drug attrition, black box warnings and post-marketing removal.

In a paper published last month in Archives of Toxicology, scientists from the two companies showed that liver spheroids produced by InSphero AG produced a fourfold better prediction of toxicity at the lowest drug concentration than 2-D cultured primary human hepatocytes when tested against 110 marketed compounds.

InSphero’s system of 3-D human liver microtissues (hLiMT) is designed to replace 2-D cell-based systems that are routinely used in industry for preclinical assessment of toxicity.

Drug-induced liver injury has been linked to nearly 1,000 marketed drugs and represents the most common cause of acute liver failure in the U.S. Adverse drug reactions are responsible for 4% of drug withdrawals in post-marketing studies and liver toxicity is a primary cause of adverse events.

Preclinical toxicology programs typically use 2-D primary human hepatocytes to detect drug liver toxicity, but the cultures lack important metabolic enzymes and transporters, and lose their liver phenotype within a few days.


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