Thyroid hormone receptor beta agonist may be safe, well tolerated in NASH
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Terns Pharmaceuticals announced positive top-line results from a phase 1 clinical trial of TERN-501, a thyroid hormone receptor beta agonist for the treatment of nonalcoholic steatohepatitis, according to a press release.
“The goal of the phase 1 study is to evaluate the safety, tolerability pharmacodynamics and pharmacokinetics of TERN-501 in healthy volunteers,” D. Barry Crittenden, MD, MS, executive director of clinical research and medical affairs at Terns Pharmaceuticals, told Healio Gastroenterology. “We are very encouraged to see a positive phase 1 safety profile and significant effects on sex hormone-binding globulin (SHBG), which is a key pharmacodynamic marker of thyroid hormone receptor beta engagement linked to NASH histologic efficacy, as well as significant reductions in atherogenic lipids including LDL cholesterol and apolipoprotein B with TERN-501.”
TERN-501 vs. placebo
During the trial, healthy volunteers were randomly assigned to placebo (n = 2) or TERN-501 (n = 6) in each cohort. Patients assigned to TERN-501 received single doses of 3 mg, 10 mg, 30 mg or 60 mg of TERN-501 in the single-ascending dose portion of the study or multiple doses of 3 mg, 6 mg or 10 mg of TERN-501 once daily for 14 days in the multiple-ascending dose portion of the study. In the drug-drug interaction portion, patients received open-label TERN-501 combined with TERN-101.
Results in the multiple-ascending dose cohort showed TERN-501 had a significant impact on key pharmacodynamic marker of thyroid hormone receptor-beta engagement correlated with NASH histologic efficacy.
According to the release, TERN-501 was safe and well tolerated. It had a predictable pharmacokinetic profile with low variability. The adverse events were mild to moderate with no correlation to dosing. No clinically meaningful differences were noted between placebo and all TERN-501 doses with regard to liver function abnormalities and mean change from baseline in liver transaminases at day 15 in the multiple-ascending dose cohorts.
Investigators noted an increase in SHBG after 14 days of treatment with TERN-501. The increases were significant, dose-dependent and correlated with robust reductions in MRI proton density fat fraction and NAFLD Activity Score in a precedent late-stage clinical NASH trial.
TERN-501 plus TERN-101 for NASH
According to the release, in the single-ascending dose cohorts, single doses of TERN-501 up to 60 mg yielded significant and dose-dependent reductions in apolipoprotein B and LDL cholesterol. In addition, significant increases in SHBG relative to placebo were noted. The combination of TERN-101 and TERN-501 was well tolerated in the drug-drug interaction cohort.
“TERN-501 demonstrated a predictable [pharmacokinetic] profile with low variability, which is promising and indicates that TERN-501 is well positioned as a candidate for combination therapy for the treatment of NASH as part of an oral, once-daily fixed-dose regimen,” Crittenden said. “In addition, preliminary [pharmacokinetic] data from a drug-drug interaction cohort assessing the combination of TERN-501 and our liver-distributed farnesoid X receptor agonist TERN-101, also in development for the treatment of NASH, support the coadministration of these agents with no apparent need for dose adjustment in future studies.
“We plan to initiate the first NASH combination trial of TERN-501 and TERN-101 in the first half of 2022,” Crittenden said. “We are looking forward to assessing the potential of this combination approach, targeting different pathophysiological pathways associated with NASH.”
Further data from the single-ascending dose cohort will be presented at The Liver Meeting Digital Experience.
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