• WVE-007 is a GalNAc-conjugated small interfering RNA (siRNA) designed to target the messenger RNA of the INHBE gene, which encodes the liver-derived protein Activin E. Activin E suppresses fat breakdown (lipolysis) by acting directly on adipose tissue. By silencing INHBE, WVE-007 aims to remove this metabolic block and restore the body’s natural fat-burning processes.
• In preclinical studies using a Diet-induced Obesity (DIO) mouse model, WVE-007 showed promise across various therapeutic scenarios—both as a standalone treatment, in combination with GLP-1 therapies, and as a maintenance option to help sustain weight loss after stopping GLP-1 therapy. 

Executive Summary

At the ADA Annual Conference in Chicago, Wave Life Sciences presented preclinical data on WVE-007, a GalNAc-conjugated siRNA targeting INHBE, which encodes the fat-burning suppressor Activin E. By silencing this gene, WVE-007 promotes fat loss, muscle preservation, and metabolic health. In DIO mouse models, the therapy demonstrated effectiveness both as monotherapy and in combination with GLP-1 receptor agonists, while also preventing weight regain after GLP-1 discontinuation.

Trial Design

In the preclinical studies, C57Bl6 mice with DIO were treated with either a single subcutaneous dose (3 mg/kg or 10 mg/kg) of INHBE-03 (a research analog of WVE-007) or control (PBS). Additional arms included co-administration with semaglutide to evaluate additive effects. Several metabolic parameters were measured, including body weight, adipocyte size, muscle mass, and macrophage infiltration. Tissue samples were analyzed histologically, and molecular endpoints such as INHBE mRNA and serum Activin E levels were quantified via RT-qPCR and immunoassays.

Results

• Weight Loss and Body Composition

A single dose of INHBE-03 led to significant weight loss, primarily driven by reductions in fat mass, without affecting muscle mass (quadriceps). At Day 28, animals treated with 10 mg/kg INHBE-03 showed marked reduction in epididymal White Adipose Tissue (epiWAT), supporting a fat-specific mechanism.

• Adipocyte Morphology and Inflammation

Histological analyses revealed decreased adipocyte diameter in mesenteric WAT, indicating reduced lipid accumulation. Additionally, INHBE-03 treatment lowered macrophage infiltration, especially pro-inflammatory M1 macrophages (CD11c+), suggesting an anti-inflammatory shift in adipose tissue.

• Synergy with GLP-1RA and Maintenance Potential

When administered with semaglutide, INHBE-03 produced approximately double the weight loss compared to semaglutide alone. Importantly, it also attenuated weight regain after GLP-1RA cessation—indicating utility as a long-acting maintenance therapy to support sustained metabolic health.

• Mechanistic Insights

The therapy significantly reduced INHBE mRNA expression and correspondingly lowered serum Activin E protein levels. Semaglutide alone had minimal effect on Activin E levels, suggesting that INHBE silencing and GLP-1RA act through complementary and independent mechanisms.

Conclusion

WVE-007 demonstrated promising preclinical efficacy as a novel metabolic therapy that triggers fat-specific weight loss while preserving muscle mass. It effectively reduces inflammatory markers in adipose tissue and enhances the impact of GLP-1RAs while mitigating rebound weight gain after their discontinuation. These findings underscore its potential as a next-generation therapeutic for obesity and associated metabolic disorders.

Future Outlook

Wave Life Sciences is advancing WVE-007 into clinical development with the ongoing INLIGHT Phase I trial. Initial human data are expected in the second half of 2025. If successful, WVE-007 could represent a durable, complementary option in obesity treatment, particularly for individuals who require long-term weight maintenance strategies following GLP-1 therapy.