Chiglitazar lowers MASH patients’ liver fat accumulation: Phase 2 trial

Treatment was approved in China in 2021 for treating type 2 diabetes

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Chiglitazar (carfloglitazar), an oral medication approved to treat type 2 diabetes in China, led to significant reductions in liver fat accumulation among people with nonalcoholic steatohepatitis (NASH), a severe form of fatty liver disease, which was recently reclassified as metabolic dysfunction-associated steatohepatitis, or MASH.

That’s according to preliminary results from the completed Phase 2 CGZ203 clinical trial (NCT05193916), which chiglitazar’s developer Shenzhen Chipscreen Biosciences announced in a company press release.

The findings show the trial met its main goal and additional data analyses are underway. The China-based company plans to present the data in more detail at an upcoming scientific conference or in a research article.

More than a quarter of the population of China have metabolic dysfunction-associated steatotic liver disease, previously known as nonalcoholic fatty liver disease, where fat deposits accumulate in the liver, called steatosis. According to Chipscreen Biosciences, about 25% of these patients will progress to a severe manifestation where steatosis gives way to liver inflammation and scarring, or fibrosis.

The risk of MASH is even higher in people with metabolic syndrome, an umbrella term for conditions that together raise the risk of heart disease, type 2 diabetes, and stroke. These conditions include high blood pressure, high blood sugar and/or cholesterol, and obesity. Managing some of them through diet is a big part of keeping MASH under control and preventing more damage to the liver.

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How does chiglitazar work in MASH?

Peroxisome proliferator activation related receptors (PPARs) is a family of proteins that help regulate a range of different biological processes including fat and sugar metabolism. They’re widely used to treat metabolic diseases such as diabetes, where they help lower blood sugar.

Different PPAR activators will target specific PPAR subtypes. Chiglitazar is a pan-activator, meaning it targets all three main PPAR subtypes. In 2021, the molecule was approved in China under the brand Bilessglu for treating type 2 diabetes that’s not effectively controlled by diet and exercise, becoming the first approved PPAR pan-activator in the world.

Beyond metabolic reactions, which are tightly linked to MASH, PPARs also regulate other MASH-related processes such as inflammation and fibrosis. For this reason, this class of medications is being studied for treating the liver disease.

Chipscreen Biosciences launched the exploratory Phase 2 CGZ203 study in 2022 to evaluate chiglitazar’s safety and preliminary efficacy against a placebo in about 100 MASH patients across sites in China. The study involved MASH patients, ages 18-75, with liver fibrosis, elevated triglycerides (a type of fatty molecule) in the blood, and resistance to insulin — the hormone that helps lower blood sugar — which is a feature of type 2 diabetes.

Participants were randomly assigned to either one of two oral doses of chiglitazar (48 or 64 mg) or a placebo once a day for 18 weeks, or about 4.5 months. The study’s main goal was to evaluate changes in liver fat content, as evaluated by a type of MRI scan.

The study met its goal, according to Chipscreen Biosciences, with both doses of chiglitazar leading to significantly greater reductions in liver fat content over 18 weeks relative to a placebo.

Both doses also showed signs of superiority to a placebo across multiple secondary trial goals. For instance, chiglitazar doses were linked to significant or dose-dependent trends toward improvement regarding the proportion of patients who achieved a reduction of least 30% in liver fat content and noninvasive biomarkers related to liver cell damage, inflammation, and fibrosis. The therapy also showed a favorable safety profile, the company said.

Other PPAR activators are being evaluated for treating MASH. Another pan-PPAR activator from Inventiva called lanifibranor is in Phase 3 clinical testing involving MASH patients with advanced liver fibrosis.