TERN-501 / Terns Pharma - LARVOL DELTA

TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial (Nature) - P2a | N=162 | DUET (NCT05415722) | Sponsor: Terns, Inc. | "Least squares mean (s.e.) changes from baseline at week 12 in MRI-PDFF with TERN-501 were: −15.4% (5.2%) with 1 mg, −27.5% (5.7%) with 3 mg (P = 0.0036) and −44.8% (5.9%) with 6 mg (P < 0.0001), versus −4.0% (5.4%) with placebo. The incidence of adverse events was similar with TERN-501 monotherapy or placebo. In conclusion, TERN-501 treatment resulted in dose-dependent, significant reductions from baseline in MRI-PDFF compared to placebo in patients with MASH."

P2a data • Metabolic Dysfunction-Associated Steatohepatitis

TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial. (PubMed, Nat Med) - P2 | "In conclusion, TERN-501 treatment resulted in dose-dependent, significant reductions from baseline in MRI-PDFF compared to placebo in patients with MASH. ClinicalTrials.gov registration: NCT05415722 ."

Clinical • Journal • Monotherapy • P2a data • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

DUET Study: A Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy and in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (clinicaltrials.gov) - P2 | N=162 | Completed | Sponsor: Terns, Inc. | Phase classification: P2a ➔ P2

Monotherapy • Phase classification • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

TERN-501 Enhances Weight Loss Efficacy of a GLP-1R Agonist in Obese Mice via Increased Fat Mass Loss without Additional Loss of Lean Mass (ADA 2024) - "Mice (~55 g BW) were treated once daily with vehicle, TERN-501 (6 mg/kg PO), semaglutide (sema, 30 nmol/kg SQ), or 501+sema for up to 6-weeks at thermal neutrality. In obese mice, TERN-501 significantly improved the efficacy of a GLP-1R agonist by normalizing EE, resulting in greater weight loss, increased fat mass loss, and relative preservation of lean mass. These results suggest that TERN-501, a potent and highly selective THRβ agonist, may be an ideal combination partner for GLP-1 therapies."

Preclinical • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity

Sex hormone binding globulin as an effective predictor of treatment response to TERN-501, a potent, highly selective thyroid hormone receptor β agonist: post-hoc analyses from a 12-week phase 2a trial (EASL-ILC 2024) - "Treatment response to TERN-501 in MASH may be effectively predicted or monitored with SHBG, potentially as early as Week 6. Patients achieving a high SHBG increase with TERN-501 treatment may not require MR-based demonstration of liver fat reduction."

P2a data • Retrospective data • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

TERN-501, a highly selective thyroid hormone receptor β agonist, significantly improved MRI-PDFF, cT1, and liver volume in clinically relevant patient populations with presumed MASH: subgroup analyses from a 12-week phase 2a trial (EASL-ILC 2024) - "12wk treatment of TERN-501 6mg, the highest dose tested in this Ph2a study significantly improved liver fat, cT1, and LV in at-risk MASH pts including those with comorbid conditions or risk factors associated with MASH. With the favorable safety profile of TERN-501 observed in the study, these analyses results support further investigation of TERN-501 in MASH pts."

Clinical • P2a data • Cardiovascular • Diabetes • Dyslipidemia • Gastrointestinal Disorder • Genetic Disorders • Hypertension • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

Novel MASH Drug Reduces Liver Fat in Mid-Stage Trial (MedPageToday) - "THR-β has emerged as an effective target, Noureddin explained, and TERN-501 is a potent, highly selective THR-β agonist that in a phase I study 'was safe, well-tolerated, and showed robust target engagement.'"

Media quote

TOPLINE RESULTS FROM A 12- WEEK PHASE 2a TRIAL (DUET) EVALUATING TERN-501, A HIGHLY SELECTIVE THYROID HORMONE RECEPTOR (THR)BETA AGONIST, EITHER AS MONOTHERAPY OR IN COMBINATION WITH TERN-101, A NONSTEROIDAL FARNESOID X RECEPTOR (FXR) AGONIST, DEMONSTRATED SIGNIFICANT REDUCTIONS IN MRBASED LIVER FAT CONTENT AND FIBROINFLAMMATION IN PATIENTS WITH PRESUMED MASH (AASLD 2023) - "12wks TERN-501 treatment significantly improved LFC and fibroinflammation in MASH pts and was well tolerated with no GI or CV AE concerns. This first placebo-controlled MASH combination trial of a THRβ and an FXR agonist met all key endpoints without additional safety findings. The compelling overall efficacy/tolerability/combinability profile of TERN-501 warrants further investigation for MASH."

Clinical • Combination therapy • Late-breaking abstract • Monotherapy • P2a data • Cardiovascular • Diabetes • Fibrosis • Gastrointestinal Disorder • Immunology • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • APOB

DUET Study: A Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy and in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a | N=162 | Completed | Sponsor: Terns, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Monotherapy • Trial completion • Hepatology • Non-alcoholic Steatohepatitis

TERN-501 Significantly Reduces NASH Liver Fat Content in Phase 2 Trial (HCPLive) - "'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,' Noureddin said. '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.'"

Media quote

Combination therapy of TERN-501, a selective agonist of thyroid hormone receptor (THR) beta with TERN-101, a farnesoid X receptor (FXR) agonist improves nonalcoholic steatohepatitis (NASH) in a GAN diet-induced and biopsy-confirmed mouse model (EASL-ILC 2023) - "Treatment with the THR-beta agonist TERN-501 in combination with the FXR agonist TERN- 101 led to greater NAS and fibrosis improvements from baseline compared with single agent treatments, likely driven by increased anti-steatotic activity. These data suggest that combining the robust anti-steatotic effects of a selective THR-beta agonist with an FXR agonist may provide a superior therapeutic benefit for NASH over either agent alone. The use of AI-digital pathology can provide granularity in NASH drug development during the preclinical phase, which may be translated to current use in NASH clinical trials."

Biopsy • Combination therapy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • Obesity

DUET Study: A Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy and in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a | N=162 | Active, not recruiting | Sponsor: Terns, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Monotherapy • Hepatology • Non-alcoholic Steatohepatitis

TRIAL IN PROGRESS: THE FIRST 12-WEEK, RANDOMIZED, CONTROLLED PHASE 2a STUDY OF A THYROID HORMONE RECEPTOR-ΒETA AGONIST (TERN-501) ADMINISTERED AS MONOTHERAPY OR IN COMBINATION WITH A FARNESOID X RECEPTOR AGONIST (TERN-101) IN PATIENTS WITH NASH (AASLD 2022) - "This is the first trial assessing safety and efficacy of a THR-β and FXR agonist combination in NASH patients. The factorial design will allow evaluation of the potential additive effects of TERN-501+TERN-101 combination compared to each agent and to placebo using noninvasive biomarkers."

Clinical • Combination therapy • Monotherapy • P2a data • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis

THYROID HORMONE BETA RECEPTOR AGONIST TERN-501 DEMONSTRATES DOSE- AND EXPOSURE-DEPENDENT INCREASES IN SEX HORMONE BINDING GLOBULIN WITH ASSOCIATED DECREASES IN ATHEROGENIC LIPIDS IN HEALTHY SUBJECTS (AASLD 2022) - "SHBG increases and lipid decreases correlated strongly with TERN-501 plasma exposure, indicating potent THR-β target engagement with 14-day TERN-501 treatment. SHBG increases of ≥75%, which have been correlated liver fat content decreases and histological improvement in THR-β agonist-treated NASH patients, were time- and dose-dependent and associated with greater reductions in atherogenic lipids in TERN-501 recipients. Predictable PK profile with low variability, robust SHBG increases, and lipid-lowering effects make TERN-501 an attractive candidate for NASH treatment and support further TERN-501 development for NASH either alone or in combination with other agents."

Clinical • Addiction (Opioid and Alcohol) • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis • APOB

DUET Study: A Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy and in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (clinicaltrials.gov) - P2a | N=140 | Recruiting | Sponsor: Terns, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology • Non-alcoholic Steatohepatitis

Multiple doses of thyroid hormone receptor-beta agonist TERN-501 were well-tolerated and resulted in significant dose-dependent changes in serum lipids and sex hormone binding globulin in a first-in-human clinical study (EASL-ILC 2022) - "Once daily TERN-501 at 3, 6, and 10 mg for 14 days was overall safe and well-tolerated. TERN-501 increased SHBG, a key marker of hepatic THR-beta engagement, in a dose-dependent fashion. Significant reductions in atherogenic serum lipids with favorable PK observed in this study support further investigation of TERN-501 for NASH treatment alone or in combination with other agents."

Clinical • P1 data • Addiction (Opioid and Alcohol) • Dyslipidemia • Endocrine Disorders • Hepatology • Non-alcoholic Steatohepatitis • APOB

A Phase 2a Clinical Study to Evaluate the Safety, Efficacy, PK and PD of Orally Administered TERN-501 as Monotherapy and in Combination With TERN-101 in Noncirrhotic Adults With Presumed (NASH) (clinicaltrials.gov) - P2a | N=140 | Not yet recruiting | Sponsor: Terns, Inc.

Combination therapy • Monotherapy • New P2a trial • Hepatology • Non-alcoholic Steatohepatitis