As obesity and diabetes patients surge, the market for treatments for metabolic dysfunction–associated steatohepatitis (MASH) is growing. However, only two treatments have been approved so far. As global pharmaceutical companies that failed to prove competitiveness against existing treatments have successively halted new drug development, attention is turning to domestic corporations that have continued development.
MASH was long called nonalcoholic steatohepatitis (NASH), but the global liver societies officially changed the name to MASH last year to emphasize metabolic factors. Metabolism refers to the process by which the body breaks down nutrients to obtain energy and excretes waste. MASH is a disease in which, unrelated to drinking, problems arise in this process, causing fat to accumulate in the liver and leading to inflammation and damage, and it can progress to cirrhosis, in which the liver hardens, and liver cancer.
Britain's AstraZeneca (AZ) said on the 6th (local time) that it halted development of the antisense oligonucleotide class investigational drug "AZD2693." In its third-quarter earnings report that day, the company said it "failed to demonstrate efficacy in a phase 2b clinical trial in patients with MASH and liver fibrosis."
Instead, it plans to focus on developing next-generation Antibody-Drug Conjugate (ADC) therapies following Enhertu (trastuzumab deruxtecan), an ADC co-developed with Japan's Daiichi Sankyo, and its follow-on drug, Datroway (datopotamab deruxtecan).
AstraZeneca is not the only one to discontinue MASH development. Earlier, U.S. drugmaker Pfizer also trimmed 11 research and development (R&D) pipeline programs, including combination therapy for MASH.
Pfizer had resumed clinical trials by combining clesacostat, which it had stopped developing in a monotherapy trial in patients with liver fibrosis, with the DGAT2 inhibitor ervogastat, but has now officially ended the project. The combination therapy had been designated for priority review (fast track) by the U.S. Food and Drug Administration (FDA) in 2022 as a candidate MASH treatment.
So far, the only MASH treatments approved by the FDA are resmetirom (resmetirom) from U.S.-based Madrigal Pharmaceuticals, first approved in March last year, and Wegovy (semaglutide) from Denmark's Novo Nordisk, which expanded its indication from obesity to MASH in Aug. However, both drugs can be used only in patients before cirrhosis, so treatments for later-stage patients are still needed.
Novo Nordisk recently halted clinical trials of two short interfering RNA (siRNA) candidates (NN-6581, NN-6582) for treating MASH. RNA replicates the genetic information of deoxyribonucleic acid (DNA) to synthesize proteins, and siRNA, a small RNA, blocks specific genes in cells from synthesizing proteins.
Instead of siRNA candidates, Novo Nordisk secured next-generation MASH treatment substances from U.S.-based Akero Therapeutics, which it acquired for 7 trillion won on the 7th of last month. Efruxifermin, a fibroblast growth factor 21 (FGF21) analog candidate under development by Akero, is currently in phase 3 clinical trials. FGF21 is a hormone secreted by the liver that lowers blood glucose and triglycerides and increases energy metabolism, fat utilization, and lipid excretion.
As global big pharma companies drop their MASH pipelines one after another, domestic corporations are emerging as new contenders.
Hanmi Pharmaceutical is developing two MASH investigational drug candidates. Independently, it is conducting a phase 2b trial in Korea and the United States of "efocipegtutide," a triple agonist of glucagon-like peptide-1 (GLP-1), glucagon (GCG), and gastric inhibitory peptide (GIP).
The other is "epinopegyutatide," a dual GLP-1 and GCG agonist, which was transferred to Merck (MSD) in 2020. With the announcement of phase 2b results due at year-end, if MSD enters phase 3, it has strong potential to grow into a blockbuster (a drug with annual sales of 1 trillion won or more).
D&D Pharmatech is also conducting a U.S. phase 2 trial of DD01, a dual GCG and GLP-1 agonist. It also received fast-track designation from the FDA. The company said interim phase 2 results showed it reduced intrahepatic fat by more than 30%. At week 12, the average fatty liver reduction rate in the DD01 arm was 62.3%, significantly higher than the placebo group (8.3%). Based on these data, the company is pursuing a global technology transfer.
OliX Pharmaceuticals, which transferred OLX702A to U.S.-based Eli Lilly for 900 billion won in Feb., is also drawing attention. OLX702A is in the same class as siRNA, which Novo Nordisk has now stopped developing. OliX Pharmaceuticals confirmed liver fat reduction effects in preclinical studies and is currently conducting a phase 1 trial in Australia for MASH and other cardiovascular and metabolic diseases.
Lilly is also independently developing Mounjaro (tirzepatide), an obesity treatment competing with Wegovy, as a MASH therapy. In addition, it is preparing to compete with Wegovy, which is being developed as a MASH treatment, with siRNA candidates transferred from OliX Pharmaceuticals.