Terns Pharmaceuticals, Inc. reported positive top-line results from the Phase 2a DUET clinical trial of TERN-501, anally-administered thyroid hormone receptor-beta (THR-b) agonist, administered as a monotherapy or in combination with TERN-101, a liver-distributed farnesoid X receptor (FXR) agonist, for the treatment of NASH. The DUET trial achieved its primary endpoint with the once-daily, orally administered TERN-501 (3 mg and 6 mg) monotherapy groups showing dose dependent and statistically significant reductions in mean relative change from baseline in liver fat content as assessed by magnetic resonance imaging, proton density fat fraction (MRI-PDFF). A liver fat content reduction of 45% was observed in the TERN-501 6 mg dose group at Week 12, compared to a 4% reduction in the placebo group (p<0.001).

Additionally, all TERN-501 monotherapy doses (1 mg, 3 mg and 6 mg) achieved statistically higher proportions of patients with MRI-PDFF reduction of at least 30% compared to placebo. MRI-PDFF response rates were dose dependent with 64% of patients treated with TERN-501 (6 mg) achieving response. A reduction in liver fat content of at least 30% based on MRI-PDFF has been shown to have a high correlation with improvements in NASH when confirmed by liver biopsy.

The Phase 2a DUET trial (NCT05415722) is a multicenter, randomized, double-blind, placebo-controlled clinical trial in noncirrhotic NASH, designed to evaluate efficacy and safety of TERN-501 as a monotherapy and in combination with TERN-101. The trial enrolled over 160 adults with body mass index (BMI) = 25 kg/m2 and pre-cirrhotic NASH identified based on prior liver biopsy and/or imaging and clinical criteria. All participants had liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) of =10%, MRI corrected T1 (cT1) relaxation time of = 800 msec and met other inclusion and exclusion criteria.

The trial included a 12-week treatment period and a 4-week follow-up period. The primary endpoint was the relative change from baseline in MRI-PDFF at Week 12 for TERN-501 monotherapy compared to placebo. Secondary endpoints included assessments of relative change from baseline in MRI-PDFF for TERN-501+TERN-101 combination compared to placebo and change from baseline in cT1 for TERN-501 monotherapy compared to placebo as well as for TERN-501+TERN-101 combination therapy compared to placebo.

TERN-501 is a thyroid hormone receptor beta (THR-ß) agonist with high metabolic stability, enhanced liver distribution and greater selectivity for THR-ß compared to other THR-ß agonists in development. Preclinical studies have demonstrated that low-doses of TERN-501 achieved complete resolution of steatosis and reductions in serum lipids and hepatic inflammation and fibrosis. TERN-501 is 23-fold more selective for THR-ß than for THR-a activation thereby minimizing the risk of cardiotoxicity and other off-target effects associated with non-selective THR stimulation.

TERN-501 has been designed to be metabolically stable and has demonstrated low pharmacokinetic variability and potential for efficacy at a low clinical dose, making it an attractive candidate for use in fixed-dose combinations for NASH treatment. Terns received Fast Track designation from the U.S. Food and Drug Administration for TERN-501 for the treatment of NASH in June 2021.