Lilly-backed Terns tees up combo trial as oral NASH drug shows promise in phase 2

Terns Pharmaceuticals is gearing up for a trial combining two NASH treatments after one of them moved the needle on some non-invasive measures of the disease in a phase 2a study. The company plans to kick off the new trial in the first half of 2022. 

The study’s primary goal was to assess safety and tolerability and not efficacy, but it included several exploratory measures that could forecast its potential to fight the liver disease. These include patients’ levels of a liver enzyme called ALT and imaging-based tests for liver fat and water content in liver tissue, which is linked to inflammation and scarring in patients with liver disease.

The 12-week study tested three dose levels of TERN-101, a farnesoid X receptor (FXR) agonist given as a daily pill, against placebo in 100 patients with non-alcoholic steatohepatitis (NASH). The patients’ disease was presumed to be non-cirrhotic, meaning it was diagnosed by non-invasive tests rather than liver biopsy. 

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After 12 weeks of treatment, the top two dose levels, 10 mg and 15 mg lowered patients’ ALT levels by 18% and 13.2%, respectively, compared to 5.3% with placebo. At week 6, the top two dose levels reduced liver fat as measured by MRI proton density fat fraction (MRI-PDFF), but these changes did not stay statistically significant relative to placebo at week 12.

The company reported the results in a press release and plans to submit the data to an upcoming scientific meeting. 

On the safety side, treatment-related side effects were mild or moderate, with no apparent link to dose levels, the company said. The patients reported no serious side effects, and no one quit the study because of a side effect. 

The most common side effects were pruritus (itchiness), headache, constipation, diarrhea, decreased appetite and dizziness. Of the 25 patients who received the lowest dose (5 mg), 16% suffered pruritus. Four of the 23 patients who received the 15 mg dose (17.4%) and three of the 26 patients who got the 10 mg dose (11.5%) suffered itching. 

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“NASH is a complex multifaceted condition, making it difficult to use just one target to treat the disease. The LIFT data are exciting because we see improvement in key non-invasive tests associated with disease severity along with an attractive safety profile with no discontinuations due to side effects,” said Rohit Loomba, M.D., director of the University of California, San Diego NAFLD Research Center and director of Hepatology at the UC San Diego School of Medicine, in the statement. “The results add to the growing body of evidence showing the promise of TERN-101 as a multi-modal therapy to treat the multiple facets of this disease.” 

In its next study, Terns will combine TERN-101 with TERN-501, its thyroid hormone receptor beta agonist that’s in a phase 1 trial due to read out by the end of the year. 

Terns figures the drug’s safety stems from its “sustained FXR activation in the liver but only transient FXR activation in the intestine.” It could help Terns surmount the hurdles that have dogged other NASH-focused companies, including Intercept, which struggled to balance safety and efficacy for its FXR agonist, obeticholic acid.