Jul 09, 2025
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
Click Here To Get the Article in PDF
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
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.
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.
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.
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.
Article in PDF
Jul 09, 2025
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
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.
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.
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.
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.