e-therapeutics plc announced new preclinical results for its GalOmic small-interfering RNA (siRNA) candidate ETX-312 at the European Association for the Study of the Liver (EASL) Congress, held May 7-10, 2025. The data supports ETX-312 as a differentiated and potentially disease-modifying treatment for metabolic dysfunction-associated steatohepatitis (MASH).
The company presented compelling results from studies using the Gubra-Amylin NASH diet-induced obese (GAN-DIO) mouse model, a leading preclinical model for MASH research. ETX-312 demonstrated significant efficacy both as a standalone therapy and when combined with other emerging treatments.
Significant Improvements in Key MASH Markers
When administered as monotherapy, ETX-312 showed dramatic improvements in NAFLD Activity Score (NAS), a key measure of disease severity. The improvements were even more pronounced when ETX-312 was combined with either a GLP-1/GIP receptor agonist or an FGF-21 analogue. All mice receiving combination therapy achieved at least 2-point reductions in NAS, with some animals showing improvements of up to 5 points.
Additionally, ETX-312 demonstrated ability to slow fibrosis progression comparable to that achieved with GLP-1/GIP receptor agonist or FGF-21 analogue controls. These findings were supported by statistically significant reductions in hepatic collagen staining and decreases in circulating biomarkers TIMP-1 and PIIINP, which are associated with fibrosis activity.
"These data add to a growing body of evidence supporting ETX-312 as a differentiated, disease-modifying therapy for MASH," said Alan Whitmore, Chief Scientific Officer at e-therapeutics. "We are excited to progress the programme towards the clinic."
Mechanism and Development Status
ETX-312 is a GalNAc-conjugated small-interfering RNA (GalNAc-siRNA) therapeutic candidate designed to silence specific gene targets in hepatocytes. The treatment is being developed with the potential for a quarterly subcutaneous dosing regimen, which could offer significant advantages for patient compliance compared to more frequently administered therapies.
The candidate is currently progressing through IND-enabling studies, with e-therapeutics on track to submit a regulatory submission by the end of 2025. The company presented these findings at EASL in a poster titled "ETX-312, a GalOmic siRNA for the treatment of MASH, effectively improves the MASH phenotype of GAN DIO-MASH mice alone or in combination with emerging therapies" (Poster Number: FRI-337).
MASH: A Growing Public Health Concern
MASH, formerly known as NASH (non-alcoholic steatohepatitis), represents the more severe form of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver inflammation and damage caused by a buildup of fat in the liver and is strongly associated with obesity, type 2 diabetes, and metabolic syndrome.
The condition affects an estimated 3-5% of the global population and can progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Despite its growing prevalence, there are currently no FDA-approved treatments specifically for MASH, highlighting the significant unmet medical need that ETX-312 aims to address.
e-therapeutics' Computational Approach to Drug Discovery
e-therapeutics combines computational power with RNAi technology to discover novel therapeutics. The company's proprietary RNAi chemistry platform, GalOmic™, enables the generation of specific, potent, and durable siRNA therapeutics for effective silencing of novel gene targets in hepatocytes.
Complementing this is the company's HepNet™ computational platform, which encompasses an extensive hepatocyte-specific knowledgebase and AI-driven approaches to identify novel gene targets and design siRNAs. This computational approach has been validated through successful drug discovery collaborations with major pharmaceutical companies including Novo Nordisk, Galapagos NV, and iTeos Therapeutics.
Broader Pipeline Development
Beyond ETX-312 for MASH, e-therapeutics is advancing a pipeline of RNAi candidates across multiple therapeutic areas with high unmet needs. The company has generated positive proof-of-concept data for preclinical assets targeting dry age-related macular degeneration (ETX-407), bleeding disorders (ETX-148), heart failure, and cardiometabolic disease.
The progress with ETX-312 represents an important milestone in the company's strategy to leverage its computational and RNAi capabilities to develop transformative medicines for patients with limited treatment options.
As ETX-312 advances toward clinical trials, the scientific community will be watching closely to see if these promising preclinical results translate to effective treatment options for MASH patients, potentially offering a new approach to addressing this challenging liver condition.
