HTD1801 Demonstrates Promising Potential for Histologic Improvements in MASH in Both a Preclinical and Phase 2 Study

Wong, Vincent Wai-Sun; Neff, Guy W.; Di Bisceglie, Adrian M.; Bai, Ru; Cheng, Junwei; Yu, Meng; Liberman, Alexander; Liu, Liping; Gunn, Nadege

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Clin Mol Hepatol > Accepted Articles

Original Article

HTD1801 Demonstrates Promising Potential for Histologic Improvements in MASH in Both a Preclinical and Phase 2 Study

Vincent Wai-Sun Wong¹

, Guy W. Neff², Adrian M. Di Bisceglie³, Ru Bai³, Junwei Cheng³, Meng Yu³, Alexander Liberman³, Liping Liu³, Nadege Gunn⁴

¹Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
²Covenant Metabolic Specialists, LLC, Florida, United States
³HighTide Therapeutics, Inc., Texas, United States
⁴Velocity Clinical Research, Waco, Texas, United States

Correspondence :

Vincent Wai-Sun Wong ,
Tel: (825) 3505-1299, Email: wongv@cuhk.edu.hk

Received: February 8, 2025 Revised: April 16, 2025 Accepted: April 17, 2025

ABSTRACT

Background & Aims
Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes (T2DM). The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence.
Methods
The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRI-PDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH Resolution Index (achieving ≥‑0.67).
Results
Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH.
Conclusions
These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.

KeyWords: noninvasive biomarkers, liver histology, MASH