Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”) is a clinical-stage biopharmaceutical company focusing on discovering and developing innovative therapies to address serious unmet medical needs in liver diseases. The Company announced the publication on its independently developed HPG 1860, a next-generation, highly effective and safe non-bile acid FXR agonist in the Journal of Medicinal Chemistry, a top international journal in the field of medicinal chemistry. The article elaborates the design strategy of lead compounds based on crystal structure, structure-activity relationship (SAR), and how to solve the side effects of obeticholic acid in clinical practice through high selectivity, targeted organ enrichment, and high drugability.

Nonalcoholic steatohepatitis (NASH) is a clinical pathological syndrome characterized by lipid accumulation, inflammation and fibrosis in the liver, caused by the parallel interactions of multiple risk factors, multiple cell types and multiple tissues and organs. NASH is prevalent worldwide, and there is currently no ideal treatment. Farnesoid X receptor (FXR), also known as bile acid receptor, is a nuclear receptor highly expressed in the gastrointestinal tract and liver. Biological studies have shown that activation of FXR can regulate the expression of many key genes involved in physiological processes such as bile acid homeostasis, inflammation, fibrosis, lipid and glucose metabolism. Clinical research has indicated that FXR agonists are expected to be promising in the treatment of NASH and other FXR-related diseases.

In order to develop safer and more effective FXR agonists for the treatment of NASH and other FXR-related diseases, Hepagene established the following principals that the new generation of FXR agonists must have the following characteristics: non-bile acid structure, full activation agonism, good metabolic stability, high selectivity and strong efficacy. As a result, HPG1860, developed by Hepagene through structural design with activity and property optimization, exhibited excellent in vitro biological activity, good in vivo exposure and oral bioavailability (52.1%~77.1%) in multiple species.

In pharmacological studies, HPG1860 significantly upregulated the expression of FXR target genes (SHP, BSEP and FGF15) in the liver and intestine of mice. In the widely used high-fat diet and carbon tetrachloride-induced NASH pharmacodynamic models, HPG1860 can effectively improve liver fibrosis and NAS scores. The recently disclosed HPG1860 Phase 2a clinical data (RISE study) reached the clinical endpoint, showing a high degree of differentiation, fully demonstrating the potential of HPG1860 to treat NASH. The results of this clinical study were also presented in the form of a poster at the 2023 European Association for the Study of the Liver Annual Meeting (EASL 2023).

Article link： https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.3c00456

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage biopharmaceutical company focusing on developing novel therapies for patients with chronic liver diseases, today announced that Hepagene will present two posters highlighting the preclinical and clinical development for its two non-alcoholic steatohepatitis (NASH) programs at the European Association for the Study of the Liver (EASL) Congress, taking place in Vienna Austria, June 21-24, 2023. Details of the presentation are as follows:

Highly Selective THR-β Agonist HPG7233
Title: Preclinical characterization of HPG7233, a potent, liver-target and highly selective thyroid hormone receptor beta agonist for nonalcoholic steatohepatitis
Presentation Number: 391
Session Title: NAFLD: Experimental and pathophysiology
Presenting Author: Dr. Que Liu (Hepagene Chief Medical Officer)
HPG7233 is a novel liver-targeted and highly selective small molecule thyroid hormone receptor beta (THR-beta) agonist aimed at serum and liver lipid metabolism. HPG7233 demonstrated high selectivity and potency, positive liver enrichment and liver plasma exposure profile in rodent and non-rodent animals, significant reduction of liver index and serological markers level, and significant reduction of NAS score in NASH model. These results provide strong evidence to support continuing efforts in HPG7233 development for NASH and dyslipidemia indications.

Next Generation Non-Bile Acid FXR Agonist HPG1860
Title: HPG1860 in patients with NASH: a phase II double-blind, placebo-controlled, dose-ranging study
Presentation Number: 383
Session: NAFLD: Therapy
Presenting Author: Dr. Naim Alkhouri (Principal Investigator)
The RISE trial, a Phase 2 study (NCT05338034), is a multi-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of orally administered HPG1860 tablet at doses of 3 mg, 5 mg and 8 mg in 87 adult patients with presumed non-cirrhotic non-alcoholic steatohepatitis (NASH). The primary objective of the clinical trial was to evaluate the safety and tolerability of HPG1860. Secondary endpoints included percent change from baseline in liver fat content (LFC) measured by MRI proton density fat fraction (MRI-PDFF), plasma pharmacokinetics of HPG1860, pharmacodynamic parameters, and serum NASH biomarkers. In the RISE trial, once daily administration of HPG1860 for 12 weeks was generally well tolerated and most AEs were mild and moderate. Treatment-related pruritus occurred in 9.1%, 9.5%, 27.3% of patients in the 3, 5, and 8mg cohort respectively and no significant change in LDL cholesterol (LDL-C) was observed in the 3 mg, 5 mg and 8 mg HPG1860 cohorts. Meanwhile, significant reductions of mean relative changes in LFC at week 12 were observed in 3 mg and 8 mg HPG1860 cohorts. Treatment of HPG1860 also reduced liver enzymes including ALT and GGT.
“We are excited about the positive progress of HPG7233, a novel once daily THR beta agonist, which may have robust efficacy with benign safety profile in clinics. The compound is on track for a Phase 1 study in the second half this year.” said Dr. Que Liu, CMO of Hepagene. “HPG1860 is a new generation of non-bile acid FXR agonist which is different from first generation bile acid type obeticholic acid (OCA). HPG1860 has shown liver enrichment profile in preclinical studies and displayed robust efficacy with much better safety profile vs OCA in clinical settings. We believe that HPG1860 in combination with HPG7233, a novel THR-beta agonist, will significantly improve efficacy while maintaining benign safety profile.”
In summary, given its significant improvement in LFC and a benign safety profile in NASH patients, HPG1860 has shown favourable risk-benefit data to support clinical development of combination therapy. Combined with favourable pharmacology, pharmacokinetic and preclinical safety profile of HPG7233, the company plans to file an IND for NASH around the third quarter of this year and is actively planning the combination study (HPG1860 and HPG7233) for NASH as well as HPG 7233 monotherapy for NASH and dyslipidemia indications.

Hepagene Therapeutics, Inc. ("Hepagene" or “the Company”) announced that the Company has received clearance from the U.S. Food and Drug Administration (FDA) to initiate clinical trials on its proprietary inhibitor of Apoptosis Proteins (IAP) antagonist, HPG3466, for patients with advanced solid tumors. 

HPG3466 is a new generation, highly effective and specific IAP antagonist developed by Hepagene with global intellectual property rights. In a variety of mouse models of human tumor cell xenografts, HPG3466 has been shown to significantly inhibit tumor growth and cause tumor regression, demonstrating better efficacy in combination therapy. Preclinical safety evaluation studies have shown that HPG3466 has good safety in rodents and non-human primates. With its excellent anti-tumor activity, positive safety profile and wide therapeutic window, HPG3466 is expected to become the best-in-class among similar targets and have great clinical development potential.

Dr. Xiaodong Xu, President and CEO of Hepagene, commented that “We are very pleased that the U.S. clinical application for HPG3466 was approved within 30 days of submission. We will accelerate the Phase I clinical trial in patients with advanced solid tumors. This is an important milestone for the Company and another practice and advancement of Hepagene’s global clinical development strategy. We look forward to the successful execution of this project, which will bring good news to patients with refractory or drug-resistant solid tumor diseases and expand its indications in viral hepatitis B in the future.”

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage biopharmaceutical company focusing on innovative therapies for patients with liver diseases, today reported positive top-line results from the Phase 2a RISE clinical trial of HPG1860, a next generation non-bile acid, liver selective farnesoid X receptor (FXR) agonist, for the treatment of non-alcoholic steatohepatitis (NASH). The trial met its primary endpoint of safety and tolerability, and HPG1860 also achieved a significant reduction in liver fat content (LFC), a key secondary endpoint.

The RISE study (NCT05338034) is a multi-center, randomized, double-blind, placebo-controlled, parallel-group, Phase 2a clinical trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of orally administered HPG1860 tablet at doses of 3 mg, 5 mg and 8 mg in 87 adult patients with presumed non-cirrhotic non-alcoholic steatohepatitis (NASH). The primary objective of the clinical trial was to evaluate the safety and tolerability of HPG1860. Secondary endpoints included percent change from baseline in LFC measured by MRI proton density fat fraction (MRI-PDFF), ALT levels, plasma pharmacokinetics of HPG1860, pharmacodynamic parameters, and serum NASH biomarkers.

In the RISE trial, once daily administration of HPG1860 for 12 weeks was generally well tolerated and most AEs were mild and moderate. Treatment-related pruritus occurred in 9.1%, 9.5%, 27.3% of patients in the 3, 5, and 8mg cohort respectively and no significant change in LDL cholesterol (LDL-C) was observed in the 3 mg, 5 mg and 8 mg HPG1860 cohorts.

Mean relative changes in LFC at week 12 were 0.68% (placebo), -20.15% (3 mg, p=0.004 vs placebo), -7.08% (5 mg, p=0.244 vs placebo), and -38.64% (8 mg, P<0.0001 vs placebo). Relatively reduced efficacy in 5 mg cohort may be due to the lower LFC at baseline vs other cohorts. For patients with ALT ≥ULN at baseline, at week 12, mean ALT percentage change from baseline in placebo, 3 mg, 5 mg and 8 mg cohort was 32.6%, -7.0%, -7.6% and -22.5% respectively, indicating dose-dependent reduction of ALT in HPG1860 treated patients.

Stephen Harrison, MD, Chairman of Summit Clinical Research whose network was responsible for enrolling this study stated, "Positive signals of LFC reduction and improvement in liver chemistry tests, along with a good safety and tolerability profile, make HPG1860 an interesting compound to study further in combination with other mechanisms of action targeting the pathogenic pathways in NASH. LDL elevations are typically seen with FXR agonists so it is encouraging to note that no significant elevations in LDL were seen in this short term trial with HPG1860."

"We are very encouraged by the significant improvement in LFC and safety profile of HPG1860. I would like to thank those who have supported enrollment in the RISE Study, especially our outstanding investigators and the patients who participated in the study." said Que Liu MD, PhD, Chief Medical Officer of Hepagene, "NASH is a multifactorial liver disease and combination therapy may be needed to achieve clinically meaningful responses and outcomes. We look forward to advancing HPG1860 clinically, including as the key component for future NASH combination treatments."

Hepagene plans to submit an abstract with detailed data from the RISE Study to an upcoming scientific conference. Based on these positive results, Hepagene continues with the current clinical development plan including a combination trial of HPG1860 with HPG7233, a thyroid hormone receptor beta agonist (THR-β) developed in house for the treatment of NASH.

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”) announced the completion of a $40 million Series B1 funding round. This round of financing was led by Loyal Valley Capital, along with Apricot Capital and Oceanpine Capital. The funds raised in this round will be primarily used for the Phase II clinical study of the farnesoid X receptor FXR agonist HPG1860 and the preclinical and clinical advancement of the company's NASH/HBV/Liver Cancer pipeline. Hepagene is a global innovative drug research and development company focused on liver diseases founded in 2016. The Company is committed to the research and development and commercialization of innovative drugs in the fields of non-alcoholic steatohepatitis (NASH), viral hepatitis B (HBV) and liver cancer to address the unmet clinical needs of patients at home and abroad.

The Company's independently developed FXR agonist HPG1860 has shown excellent safety and unique competitive advantages in the Phase I clinical data in the United States. Hepagene is currently actively preparing for Phase II clinical trials for indications such as non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), as well as clinical studies on combination drugs based on HPG1860.

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage biopharmaceutical company focusing on innovative therapies for patients with liver diseases, today announced that it has screened the first patient in the USA for the RISE study, a Phase IIa clinical trial of HPG1860 in patients with non-alcoholic steatohepatitis (NASH). HPG1860, a non-bile acid, potent, selective and full farnesoid X receptor (FXR) agonist, is under development for the treatment of NASH and cholestatic hepatitis.

"We are thrilled to initiate the HPG1860 Phase IIa RISE trial in NASH patients. We have recently reported positive Phase I data of HPG1860 at the 2021 AASLD meeting. HPG1860 displayed a benign safety profile with robust target engagement through C4 reduction and FGF19 activation." said Dr. Que Liu, Chief Medical Officer of Hepagene. "We look forward to assessing safety and efficacy of HPG1860 in the RISE study and advancing HPG1860 as a potential therapy for NASH patients."

The RISE study is a 12-week, randomized, double-blind, placebo-controlled multi-center Phase IIa clinical trial evaluating the safety, tolerability, and efficacy in NASH patients who receive placebo or 3mg, 5mg and 8 mg doses of HPG1860. The trial will enroll 80 patients (20 patients/cohort) in the USA. Each study drug (placebo or HPG1860) will be given once daily by oral administration. The primary endpoint for the study is the safety and tolerability of HPG1860, while the secondary endpoint is to assess changes in liver fat content (LFC) after treatment with HPG1860. Other endpoints include changes in biomarkers and pharmacokinetic profile of HPG1860 in NASH patients.

"Initiating RISE Phase IIa trial in NASH patients represents an important milestone for Hepagene." said Dr. Michael X. Xu, CEO of Hepagene. "Our focus is on liver diseases, and we anticipate multiple novel mechanism compounds for both NASH and HBV entering clinical trials in the near future. At the same time, we are actively advancing pipelines utilizing in house developed novel siRNA delivery platform."

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage biopharmaceutical company focusing on innovative therapies for patients with liver diseases, today announced three key additions to its Scientific Advisory Board. The addition of three internationally influential experts in the field of NASH and PBC will help Hepagene advance the Phase II/III clinical program of HPG1860, as well as accelerate the clinical advancement of multiple liver disease projects in the company's pipeline.

Professor Eric Gershwin, a renowned expert in the field of PBC at the University of California. He has written more than 900 experimental papers and more than 20 professional books. Dr. Eric Gershwin has extensive experience in clinical research and has led multiple clinical studies on the treatment of autoimmune diseases, including PBC.

Dr. Rohit Loomba is a an internationally recognized leader in translational research and innovative clinical trial design in non-alcoholic steatohepatitis (NASH). He is currently a professor at the University of California, San Francisco. Dr. Loomba is the founding director of the UC San Diego NAFLD Research Center and serves on various committees of the American Society of Liver Diseases (AASLD).

Professor Stephen Harrison is an internationally renowned expert in non-alcoholic fatty liver disease research and has published more than 250 peer-reviewed publications in this field. Stephen A. Harrison, MD, is the Medical Director for Pinnacle Clinical Research and the President of Summit Clinical Research.

Dr. Xiaodong Xu, President of the Company, said, "Hepagene is committed to the research and development of liver diseases. We are very pleased that these three outstanding scientists have joined the company's scientific advisory board. Their joining is a high recognition of the company's product pipeline. I believe that as the scientific advisory board team grows, it will surely promote the rapid advancement of the company's clinical projects. We look forward to working closely with them."

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage biopharmaceutical company focusing on novel therapies for patients with liver diseases, today announced positive results from its Phase I study of HPG1860 conducted in the United States. HPG1860 is a non-bile acid, potent, selective and full FXR agonist being developed for treatment of non-alcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC). Findings show that treatment with HPG1860 was safe, well-tolerated and demonstrated a robust target engagement with a favorable pharmacokinetic (PK) profile after 14 days of once daily dosing in healthy volunteers. Detailed results will be presented at upcoming AASLD international liver conference.

The Hepagene Phase I trial was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD) and multiple-ascending dose (MAD) trial, in which healthy volunteers received once-daily HPG1860 doses ranging from 10 mg to 100 mg in the SAD cohorts and 5 mg to 20 mg in the MAD cohorts for 14 days. The primary objective of the trial was to evaluate safety/tolerability and the secondary objectives were to assess PK parameters and FXR target engagement, the latter through measurement of fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4), blood biomarkers of bile acid synthesis and metabolic homeostasis that increases and decreases respectively with FXR activation.

HPG1860 was safe and generally well-tolerated with no serious adverse events reported. Most adverse events were mild in severity. Importantly, pruritus only occurred in highest dose cohort (20 mg) and LDL-cholesterol increases were not seen at any dose level. HPG1860 exhibited a favorable PK profile as well as robust FXR target engagement with notable C4 regression – 93.1%, 97.0% and 97.6% decrease observed after the last dose in MAD 5 mg, 10 mg and 20 mg cohorts compared with placebo. The magnitude of C4 decrease can be used to project potential liver fat reduction level in NASH patients, with ≥ 30% relative liver fat reduction being associated with increased likelihood of histological benefits upon liver biopsy.

"We are encouraged by the overall safety profile of HPG1860, and meaningful target engagement seen at as low as the 5 mg dose level. We plan to evaluate the 3 mg, 5mg and 8 mg dose levels in our upcoming Phase IIa trial in NASH patients," said Que Liu, M.D., PhD, Chief Medical Officer of Hepagene.

"It is encouraging to see that there was no significant increase in LDL cholesterol despite excellent FXR target engagement with sustained C4 suppression." said Rohit Loomba, MD, MHSc, Professor of Medicine, and Director, UCSD NAFLD Research Center, University of California at San Diego, La Jolla, CA.

"NASH is a complex liver disease with multiple pathways involved in liver cell injury, inflammation and fibrosis development. FXRs have been shown to impact the underlying pathology of NASH in a meaningful way. Combination therapy, involving multiple mechanisms of action, is likely going to be needed to combat this disease effectively, providing an opportunity for HPG1860. The early data presented here are very encouraging from a safety and tolerability perspective and I am looking forward to beginning the Phase 2 study," said Stephen Harrison, MD, Medical Director of Pinnacle Clinical Research in San Antonio, Texas.

Based on the Phase 1 safety and PK/PD data, Hepagene plans to advance three dose levels of HPG1860 3 mg, 5 mg and 8 mg in a 12-week, randomized, placebo-controlled Phase IIa trial enrolling about 80 patients with NASH in US. The selected doses are projected to inhibit C4 to levels that are likely to result in meaningful reductions in liver fat content. The trial is scheduled to start in the last quarter of 2021, with an interim analysis planned in the first half of 2022.

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”) announced that the Company has completed the single and multiple repeated dosing in the Phase I clinical trial in US for HPG1860. Preliminary analysis of clinical data showed that HPG1860 has good safety, excellent pharmacokinetic characteristics and significant target-related effects, supporting the once-a-day oral dose in clinical practices.

HPG1860 is a non-bile acid structure, highly efficient, highly selective full farnesoid X receptor agonist, developed by Hepagene with global intellectual property rights. HPG1860's Phase I clinical study in the United States has shown that all doses in single and multiple dose trials have demonstrated (1) good safety and tolerability; (2) good PK properties, and (3) outstanding and significant target engagement of biomarkers highly relevant to efficacy (C4 and FGF19), among which C4 showed sustained target engagement effects. Currently, Hepagene is actively preparing for global Phase II clinical studies (expected to start in the United States in the second quarter of 2021) for NASH, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), including combination drug studies based on HPG1860. The Company will release the results of the Phase I clinical trial at the 2021 AASLD Annual Meeting. 

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”) announced today that it has received approval from NMPA for clinical trials of its proprietary novel drug candidate HPG1860 for the treatment of non-alcoholic steatohepatitis (NASH) in China.

HPG1860 is a non-bile acid structured, highly potent, and highly selective full farnesoid X receptor agonist independently developed by Hepagene Therapeutics, Inc. with global intellectual property rights. It is highly efficacious and at the same time displayed highly differentiated pruritus and LDL profile in clinical trials. In the Phase I trial conducted in US, HPG1860 has shown, in both single and multiple doses, (1) good safety and tolerability; (2) good PK properties; and (3) significant target engagement with biomarkers (C4 and FGF19) known to be highly relevant to therapeutic efficacy. Currently, Hepagene is actively preparing for Phase II clinical studies on NASH, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) worldwide, including HPG1860-based combination drug studies. 

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease in the world. According to surveys, the prevalence of NAFLD in ordinary adults is 10% to 30%, of which 10% to 20% is NASH, and the incidence of the latter developing into cirrhosis within 10 years is as high as 25%. Non-alcoholic fatty liver disease has now become an important cause of chronic liver disease and liver transplantation in China. Currently, there is no drug approved for the treatment of NASH in the world.

Hepagene Therapeutics, Inc. (“Hepagene” or “the Company”), a clinical stage drug discovery and development company which devotes its efforts towards discovering, developing and delivering innovative medicines that help patients prevail over liver diseases, announced today that it has dosed the 1st healthy volunteer in a Phase I clinical trial of HPG1860 in the United States. HPG1860 is a non-bile acid, potent, selective and full farnesoid X receptor (FXR) agonist.

Hepagene's Phase I study of HPG1860, titled, "A Randomized, Double-Blind, Placebo Controlled, Sequential Parallel Group, Single and Multiple Ascending Doses (SAD/MAD) Study following Oral Administration in Healthy Subjects to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HPG1860", is to assess the safety, tolerability and pharmacokinetics and pharmacodynamics in single- and multiple ascending dosed healthy volunteers. The study will also evaluate the food effect of HPG1860 in healthy subjects.

"HPG1860 is a non-bile acid FXR agonist and exhibits excellent differentiation profiles based on our preclinical research study," stated Dr. Michael X. Xu, Hepagene's CEO, "The primary goal of HPG1860 Phase I study is to understand the drug safety profile. At the same time, the results from PD biomarker study will help to establish a safe and efficacious dose for Phase II study. PBC/PSC indication will also be considered for HPG1860."