MASH Fibrosis as Unmet Medical Need

Liver fibrosis represents a common final pathway of virtually all chronic liver diseases, including Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD) and associated MASH. NAFLD, affecting around one-fourth of the general world population, represents a global health burden and a great challenge to treat, because it is associated with a number of serious co-morbidities such as metabolic syndrome, diabetes, cardiovascular disease, dyslipidemia (Perumpail et al, 2017). If left untreated, in 15%-20% of patients will progress to MASH. MASH is further associated with a spectrum of serious complications that include progressive fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC) (Lambrecht & Tacke, 2021). It is estimated that MASH currently affects around 1.5%-6.5% of the general population, and its prevalence is rising (Younossi et al, 2016).

There are currently no FDA-approved medications for the treatment of MASH and associated fibrosis despite significant drug development efforts by the pharmaceutical industry to bring safe and effective treatments to market. As advanced MASH fibrosis is recognized as a major driver for long-term morbidity outcome and mortality (Castera et al, 2019), it represents significant unmet need for effective anti-fibrotic agents.

Mechanism of Action of Hydronidone Supports Its Development in MASH Fibrosis

Gyre believes that Hydronidone may offer a potent anti-fibrotic therapeutic option for MASH fibrosis. The key attributes of the molecular mechanism of action of Hydronidone that support the proposed clinical investigation in MASH fibrosis include inhibition of Hepatic Stellate Cells (HSCs) activation via Smad7-mediated TGFβRI degradation that led in animal liver fibrosis model to attenuation of liver fibrosis, decreased collagen accumulation, and reduced the expression of fibrosis-related genes in HSCs (Xu X et al. Liver International 2023). Activated HSCs are recognized as a critical player in fibrogenesis in the liver. In addition, inhibition of both p38γ kinase activity and inhibition of proliferation of HSCs, all recognized as critical events in the development and progression of fibrosis in the liver, were also observed in mechanistic studies of Hydronidone (data on file). Furthermore, the in vitro anti-fibrotic effects of Hydronidone were also translated in several established in vivo models of liver fibrosis, including animal model of MASH fibrosis. Specifically, in a simple murine MASH model by using Western diet (WD) and carbon tetrachloride (CCl₄) that develops histological features of severe MASH with rapid progression of extensive fibrosis, Hydronidone showed protective effects in a dose range of 15 – 50 mg/kg by reducing MASH score, and significantly inhibiting the CCl₄ and WD-induced fibrosis and cell ballooning. These doses are considered to be relevant to the doses studied in the completed Phase 2 clinical study in patients with chronic Hepatitis B liver fibrosis.

Proposed Development Plan of Hydronidone in MASH fibrosis in the US

The development of Hydrondione in MASH fibrosis is expected to be initiated by a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, clinical study in patients with presumed MASH and advanced liver fibrosis. The study will be a multi-center, outpatient trial that will be conducted in multiple clinical research sites in the United States. The primary objective of this study is to assess pharmacodynamic (early proof-of-concept (PoC) effects of Hydronidone capsules in advanced non-cirrhotic MASH fibrosis, as determined by use of non-invasive, disease-specific biomarkers of MASH fibrosis (combination of laboratory and imaging modalities), in the context of drug exposure over 24 weeks. This is an exploratory study designed to evaluate the safety of Hydronidone and identify signals of efficacy.

Upon results from the Phase 2a study, if positive trends are observed, Gyre may consider either expansion either in a larger Phase 2 liver-biopsy based clinical trial, or in combination with an agent with complimentary mechanism of action.

Publications

Xu X, Guo Y, Luo X, Shen Z, Sun Z, Shen B, Zhou C, Wang J, Lu J, Zhang Q, Ye Y. Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI. Liver International. 2023.

Cai X, Liu X, Xie W, Ma A, Tan Y, Shang J, Zhang J, Chen C, Yu Y, Qu Y, Zhang L. Hydronidone for the treatment of liver fibrosis related to chronic hepatitis B: a phase 2 randomized controlled trial. Clinical Gastroenterology and Hepatology. 2023 Jul 1;21(7):1893-901.

Zhang R, Li P, Guo P, Zhou J, Wan J, Yang C, Zhou J, Liu Y, Shi S. A Pharmacokinetic Drug–Drug Interactions Study between Entecavir and Hydronidone, a Potential Novel Antifibrotic Small Molecule, in Healthy Male Volunteers. Advances in Therapy. 2023 Feb;40(2):658-70.

Zhang R, Li P, Zhou J, Guo P, Liu Y, Shi S. A novel, simple and reliable method for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine by HPLC-MS/MS and its application to a pharmacokinetic study in health Chinese subjects. Analytical Biochemistry. 2022 Oct 15;655:114842.

Liu Y, Wu J, Li Z, Luo Y, Zeng F, Shi S. Tolerability and pharmacokinetics of hydronidone, an antifibrotic agent for hepatic fibrosis, after single and multiple doses in healthy subjects: an open-label, randomized, dose-escalating, first-in-human study. European journal of drug metabolism and pharmacokinetics. 2017 Feb;42:37-48.