THR-α

HONG KONG and NANJING, China, Sept. 20, 2023 /PRNewswire/ -- Hepagene Therapeutics, Inc. a clinical-stage biopharmaceutical company today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for its HPG7233, an agonist of Thyroid Hormone Receptor beta (THR-β) for the treatment of patients with non-alcoholic steatohepatitis (NASH) and dyslipidemia. HPG7233 is a highly selective small molecule thyroid hormone receptor beta (THR-β) agonist with liver enrichment profile. In preclinical studies, HPG7233 demonstrated high selectivity and potency, significant reduction of liver triglyceride and serum LDL-C in the relevant animal models. More importantly, remarkable synergistic effect has been observed in the combination groups, especially in combination with HPG1860 (Hepagene's internal Phase II FXR agonist). HPG7233 has excellent target tissue selectivity and has shown good safety and tolerability in the toxicology studies with no adverse findings related to THR-α subtypes or in gastrointestinal tract. These results provide strong evidence to support continuing efforts in HPG7233 clinical development. "We are delighted that FDA has cleared the IND application for HPG7233, which expands our NASH pipeline and represents another important milestone for Hepagene." said Michael X. Xu, PhD, President and CEO of Hepagene, "We plan to initiate HPG7233 clinical study soon and look forward to implementation of this project successfully. To improve the modest efficacy observed with first generation of NASH candidates, we will also actively explore combo studies of THR-β agonist with internal FXR and/or GLP-1R agonist." Based on its superior preclinical profile, HPG7233 has great potential to become the next generation of THR-β agonist to benefit patients with NASH and dyslipidemia. About HPG7233 THR-β isoform is mainly expressed in the liver. The activation of THR-β is beneficial to the reduction of liver fat and the improvement of dyslipidemia. HPG7233 is a novel liver-targeted and highly selective small molecule thyroid hormone receptor beta (THR-β) agonist aimed at serum and liver lipid metabolism. HPG7233 demonstrates high selectivity and potency, great liver-enrichment and liver/plasma exposure profile in rodent and non-rodent animals, significant reduction of liver triglyceride and serum LDL-C and significant reduction of NAS score in NASH model. About Hepagene Therapeutics, Inc. Hepagene Therapeutics, Inc. a clinical-stage biopharmaceutical company, devotes its drug discovery and development efforts towards discovering, developing and delivering innovative medicines that help patients prevail over liver diseases and other life-threatening diseases, especially non-alcoholic steatohepatitis (NASH), chronic Hepatitis B infection (HBV), liver cancer or advanced solid tumors. For further information, please contact: Ms. Tao [email protected] SOURCE Hepagene Therapeutics, Inc.

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 pro 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. Placebo N=21 TERN-501 1mg 3mg 6mg At Week 12 N=23 N=19 N=22 MRI-PDFF 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 pro 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 pro 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. About TERN-501 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: . Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements about Terns Pharmaceuticals, Inc. 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A study expands the list of known genes with circadian variation and provides the first comprehensive list of genes with seasonal variation in each tissue. Tissues in the thoracic cavity, such as the lung and heart, were most sensitive to day-night cycles, while the brain and testes were most sensitive to seasonal changes. The researchers identified 91 day-night genes and 307 seasonal genes that are known-targets for drugs, including 11 chemotherapies. The drugs could benefit from being administered in a time or season-dependent manner. The daily rotation of Earth and its yearly voyage around the Sun marks the natural rhythm of life on the planet. Human health indicators such as body temperature, blood pressure and sleep, as well as animal behaviour including foraging, moulting, mating or hibernating, is influenced by innate biological clocks that work over circadian (day-night and twenty-four hour) and/or circannual (seasons and twelve-month) cycles. A research team led by Dr. Manuel Irimia and Dr. Roderic Guigó at the Centre for Genomic Regulation (CRG) in Barcelona have published research in PLOS Biology which details how the circadian and circannual cycles influence humans at the molecular level by measuring changes to the activity of genes inside cells across different types of tissues. The researchers studied gene expression, a vital process by which the information encoded in genes is used to create useful products like proteins, which cells, tissues and organs require to stay alive and function properly. Alterations to gene expression can benefit or have adverse effects for human health, which is why researchers study which factors regulate the process to develop effective diagnostic and therapeutic strategies. The study analysed gene expression data from 46 different human tissues provided by 932 donors for the Genotype-Tissue Expression (GTEx) project, a database and tissue bank used by the scientific community to explore the effects of gene expression and variation on human health and disease. Measurements for the GTEx project are taken when a donor dies, and the authors of the study used time and season of death in the metadata of the project to assess the impact of circadian and circannual variation on gene expression across the human body. Unlike other studies that could only infer time of death, GTEx data provides the exact time -- a measurement that is important for the validity of the findings. The analysis revealed that tissues in the thoracic cavity had the largest number of day-night genes, including the lung (17.2% of all genes expressed in the tissue) and the left ventricle of the heart (19.2%), which can be explained by differences in heart rate and breathing patterns between day and night. In contrast, only 85 genes in the salivary glands showed circadian variation (0.63%), followed by 92 in the transverse colon (0.67%) and 105 in the testis (0.66%). The researchers next examined the ratio of day vs. night genes within each tissue. This revealed that the stomach has a strong diurnal preference for gene expression, whereas skin that hasn't been exposed to sun showed strongest nocturnal preferences. As expected, sun-exposed skin showed the opposite effect and had a diurnal preference, which may be because ultraviolet light alters gene expression inside cells. The authors of the study also created a list of 445 genes with a consistent day or night pattern across multiple tissues. The list includes "clock genes" already known to play an essential role in the circadian rhythm and which control when humans are awake and active.The authors found that expression variation of clock genes is also conserved in baboons and mice, although in the case of mice the clock is inverted, as expected from a nocturnal animal. The list also revealed many genes not previously known to vary during the day-night cycle. One example is THRA, a thyroid hormone receptor that was found to peak at night in 15 different types of human tissues. Another example is TRIM22, which peaks during the day and which is known to be expressed in response to viral infections, restricting their ability to replicate, for example by inhibiting the transcription of HIV-1. The effect of seasonality on gene expression revealed that twelve-month variation has a similar size of effect to 24-hour variation. The highest proportion of seasonal genes were found in the testes (25.6%) -- one of the tissues with lowest proportion of day-night genes -- followed by multiple subregions of the brain. In contrast, the left ventricle of the heart showed the lowest level of seasonality (2.8%). "We found that day-night and seasonal variation are largely uncoupled. Brain and gonadal tissues exhibited the highest seasonality, whereas those in the thoracic cavity showed stronger day-night regulation. This shows that not only genes, but also tissues, are differently affected by day-night and seasonal variation," explains ICREA Research Professor Manuel Irimia, co-author of the study and researcher at the Centre for Genomic Regulation. Most tissues did not show any bias for season-specific changes in gene expression except for the testes, which showed massive increases in gene expression during autumn and decreases in spring. The finding could reflect seasonal changes in gonadal function. The authors created a list of 1,748 unique genes with a consistent seasonal pattern across multiple tissues -- 308 in spring, 361 in summer, 1,072 in autumn and 322 in winter. Many of these genes are linked to immune function and their expression is boosted in autumn and winter, consistent with the seasonality of viral infections. Some genes were also linked to the activity of hormones in the hypothalamus and pituitary glands. For example, pituitary hormone genes peaked during the summer months. The list revealed seasonal fluctuations of genes previously linked to various disorders. For example, the expression of Glioma tumor suppressor candidate region gene 1 (GLTSCR1) increases in autumn across 16 different types of tissues, including in the brain's cerebral hemisphere. GLTSCR1 has previously been linked to intellectual disability disorders. Researchers also found that the expression of Keratin 1 (KRT1) decreases in winter across 24 different types of tissues. KRT1 mutations in mice have previously been linked to the production of abnormal levels of proteins that regulate the immune system, as well as aberrant pigmentation in skin. Previous studies have shown that seasonal changes can alter the structural arrangement of neurons and other cell types within the central nervous system. The researchers used the study to explore this at the gene expression level, and found patterns that suggest that the volume and relative arrangement of brain cells including neurons, astrocytes and oligodendrocytes change in particular subregions of the brain. For example, the expression of astrocytes, cells which support neurons, increased in autumn and winter and generally fell in summer. Further research could assess the functional impact of this finding and whether it is linked to seasonal patterns of psychiatric and brain diseases. Finally, the researchers compared their list of 445 day-night genes and the list of 1,748 seasonal genes with a database that includes known gene targets for drugs treating various types of diseases. They found that 91 day-night genes (20%) are currently being targeted by 1,071 different drugs, each of which could stand to benefit from being administered at the right time of day. They also found that 307 seasonal genes (18%) are targeted by 2,632 different drugs, each of which could stand to benefit from being administered at the right season -- summer, autumn, winter or spring. This included 11 anticancer drugs including bortezomib, which targets 16 genes and cisplatin, which targets 15. It also included an anticancer drug still in clinical trial phase. "These findings have implications for administering drugs that target specific genes in specific body parts. For example, the higher the expression of a gene during a particular time of day, the larger dose is required to block their action. Administering a drug could be timed to best match the circadian pattern of gene expression. Our findings could also have an impact on clinical trials, as the effect of the same drug dose may change depending on the season of the year," says Dr. Roderic Guigó, co-author of the study and researcher at the Centre for Genomic Regulation.