Terns Achieves Primary Endpoint and All Secondary Endpoints in Phase 2a DUET Trial of THR-β Agonist TERN-501 in NASH
TERN-501 demonstrated dose dependent MRI-PDFF reductions at Week 12 as a once-daily, low dose, and combinable oral therapy
TERN-501 (6mg) showed statistically significant mean relative liver fat content reduction of 45% as assessed by MRI-PDFF with 64% of patients achieving >30% PDFF reduction
All TERN-501 doses were well-tolerated with no gastrointestinal and no cardiovascular safety signals
Company to host conference call and webcast at 4:30 pm ET today
FOSTER CITY, Calif., Aug. 08, 2023 (GLOBE NEWSWIRE) -- Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq: TERN), a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology, non-alcoholic steatohepatitis (NASH) and obesity, today reported positive top-line results from the Phase 2a DUET clinical trial of TERN-501, an orally-administered thyroid hormone receptor-beta (THR-β) 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.
“TERN-501 demonstrated highly encouraging efficacy results in MRI-PDFF reductions. The high degree of liver fat content reduction alongside the class-leading safety profile observed in the DUET trial create the potential for TERN-501 to be the THR-β monotherapy of choice and possibly a mainstay backbone of NASH combination therapies,” said Erin Quirk, M.D., president and head of research and development at Terns. “We sincerely thank all those who helped rapidly advance the DUET trial, including our dedicated team of investigators and clinical sites, the outstanding members of the Terns team, and, most importantly, the patients who participated in the trial.”
Primary and secondary TERN-501 monotherapy efficacy results at Week 12 are summarized below.
|At Week 12||N=23||N=19||N=22|
|Mean baseline (%)||17||16.6||19.5||17.3|
|Relative change (%) from BL||-4||-15||-27**||-45***|
|Absolute change (%) from BL||-1||-3||-5**||-8***|
|Patients (%) achieving ≥30% relative reduction||4%||26%*||39%**||64%***|
*p<0.05, **p<0.01, ***p<0.001 versus placebo
- TERN-501 (6 mg) monotherapy demonstrated a statistically significant reduction in the secondary endpoint of a mean change in corrected T1 (cT1), a magnetic resonance-based imaging marker of liver fibro-inflammation correlated with clinical outcomes in patients with liver disease.
- TERN-501 monotherapy demonstrated improvement or trends toward improvement in plasma lipid parameters, such as LDL-C, HDL-C, triglycerides, and apolipoprotein B (ApoB).
- There were dose dependent increases in sex hormone binding globulin (SHBG), a marker of THR-β agonism in the liver; the mean SHBG increase with TERN-501 (6 mg) exceeded 120% at Week 12 and was statistically greater than placebo (p<0.001).
DUET TERN-501 safety findings:
- TERN-501 was generally well tolerated, with adverse events (AEs) being generally mild and evenly distributed across all arms, including placebo. There were no drug-related serious adverse events (SAEs).
- Drug-related AEs of interest were similar across all arms, including placebo, with similar rates of GI events, including nausea, diarrhea and vomiting. No drug-related cardiovascular AEs were observed.
- Mean change in thyroid axis hormones, including thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4), and liver enzymes, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyltransferase (GGT), at Week 12 were similar to placebo.
DUET TERN-501 + TERN-101 combination findings:
- The combination of TERN-501 and TERN-101 (10 mg) resulted in modest improvements in MRI-PDFF mean relative change (6 mg of TERN-501 combo) and >30% MRI-PDFF responder rate (3 mg and 6 mg of TERN-501 combo) when compared to TERN-501 monotherapy arms in Week 12. cT1 results were comparable across mono and combo treatment arms.
- The combination of TERN-501 and TERN 101 (10 mg) did not result in LDL increases from baseline at Week 12, suggesting TERN-501 was able to reverse FXR-mediated LDL increases.
- Overall, these results are supportive of the ability to administer TERN-501 in combination with FXR and potentially other therapeutics.
- There were no treatment-emergent safety signals from the combination arms. TERN-101 safety and tolerability findings were generally consistent with the Phase 2a LIFT trial.
“With no FDA approved therapies, THR-β represents a key mechanism of action for the treatment of NASH, as it is the only class of treatment to have demonstrated both resolution of steatohepatitis and improvement in fibrosis in a registrational NASH study. TERN-501's impressive efficacy within a short duration and excellent safety profile is compelling especially with its once-daily, oral dosing as well as its cardiovascular and GI safety profile, the latter of which has adversely affected other NASH modalities in development,” said Mazen Noureddin, M.D., MHSc, Professor of Clinical Medicine, Academic Institute, Houston Methodist, Director of Houston Research Institute, and a principal investigator in the DUET trial. “These results add to the growing body of evidence of the safety and efficacy profile of TERN-501 and its promise as a therapy to treat the multiple facets of this disease.”
Terns plans to submit data from the DUET trial for presentation at an upcoming scientific conference.
Investor Conference Call
Terns will host an update call for investors today, August 8, 2023, beginning at 4:30 p.m. ET. The webcast of the conference call can be accessed here. A replay of the call will also be available on the Events page of the Investor Relations section of the Terns website for 30 days.
About the Phase 2a DUET Trial
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-β) agonist with high metabolic stability, enhanced liver distribution and greater selectivity for THR-β compared to other THR-β 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-β than for THR-α 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.
About Non-alcoholic Steatohepatitis (NASH)
NASH is a severe form of non-alcoholic fatty liver disease (NAFLD) that affects up to 20 million people in the United States, and up to 5% of the global population, and for which there is currently no approved therapy in the United States or Europe. In a study published in Hepatology in 2018, lifetime costs of treating and managing NASH patients in the United States in 2017 were estimated to be over $220 billion, in the absence of approved therapies. NASH is a multifaceted disease that involves three distinct pathogenic hepatic disease processes: accumulation of excess fat in the liver (steatosis), inflammation and fibrosis. In addition to these three disease processes, NASH patients often exhibit elevated levels of glucose and atherogenic lipids, are overweight or obese and accumulate excessive lipotoxic fat. Severe progression of NASH can lead to cirrhosis, decompensated liver disease and increased risk for hepatic carcinoma and liver-related mortality.
About Terns Pharmaceuticals
Terns Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing a portfolio of small-molecule product candidates to address serious diseases, including oncology, NASH and obesity. Terns’ pipeline includes two clinical stage development programs including an allosteric BCR-ABL inhibitor and a THR-β agonist (+/- an FXR agonist), and preclinical small-molecule GLP-1 receptor agonist and GIPR modulator programs. For more information, please visit: www.ternspharma.com.
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