Presentation to highlight WVE-007 (INHBE GalNAc-siRNA) as a potential novel and unique obesity treatment leading to healthy weight loss and supporting preclinical data demonstrating potent and durable reduction in Activin E resulting in fat loss with muscle preservation

New preclinical data demonstrate that a single dose of INHBE siRNA leads to lower inflammation of adipose tissue with strong suppression of pro-inflammatory M1 macrophages in visceral fat in DIO mice, highlighting potential mechanistic insights into the risk reduction for type 2 diabetes (T2D) and coronary artery disease (CAD) suggested by human genetics

CAMBRIDGE, Mass., June 20, 2025 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced the presentation of preclinical data supporting WVE-007, its GalNAc-siRNA designed to silence INHBE mRNA, an obesity target with strong evidence from human genetics. The data demonstrate the ability of Wave’s long-acting GalNAc-siRNA to reduce INHBE mRNA and Activin E protein, induce weight loss mainly through reduction of fat mass, and reduce pro-inflammatory macrophage recruitment in a diet-induced obese (DIO) mouse model. The data were highlighted today in an oral presentation at the American Diabetes Association’s 85^th Annual Scientific Sessions, taking place June 20 to 23, in Chicago.

“These exciting preclinical data highlighted in today’s presentation both recapitulate human genetics findings and continue to support the potential of WVE-007 to drive weight reduction by reducing Activin E to induce lipolysis – or fat breakdown, preferentially reducing visceral fat, and decreasing inflammation of adipose tissue – all without impacting lean muscle mass. These data suggest a highly differentiated therapeutic profile with lower visceral fat, less insulin resistance and less inflammation, supporting potential for risk reduction of T2D, CAD and other obesity-related co-morbidities,” said Erik Ingelsson, MD, PhD, Chief Scientific Officer. “Silencing of INHBE is an entirely orthogonal mechanism from GLP-1s, which are centrally acting and impact the digestive system and central nervous system to decrease appetite. If these preclinical data translate in the clinic, WVE-007 has the potential to transform the obesity treatment paradigm by delivering healthy weight loss, preservation of muscle mass, and infrequent dosing of once or twice a year. We are evaluating WVE-007 in our ongoing INLIGHT clinical trial in adults living with overweight or obesity, and we are on track to deliver the first clinical data in the second half of this year.”

Human genetics provides strong evidence for INHBE as a therapeutic target. Individuals who have a protective loss-of-function variant in one copy of the INHBE gene have a healthier cardiometabolic profile, including less abdominal fat, lower triglycerides, and lower risk of type 2 diabetes and cardiovascular disease. These heterozygous carriers also exhibit favorable associations with liver traits, including reductions in cT1 (reflecting liver inflammation and fibrosis) and ALT (reflecting liver damage), with no impact on liver fat.

The oral presentation titled, “siRNA-INHBE Silencing in Mice Recapitulates Human Genetic Data and Demonstrates Improved Healthy Weight Loss Profile,” highlighted results from studies in DIO mice that evaluated monotherapy (INHBE-siRNA alone) as well as combination (INHBE siRNA and semaglutide), and maintenance (INHBE siRNA when semaglutide treatment is discontinued) treatment settings. Key results are as follows:

• A single dose of INHBE-siRNA led to robust target engagement, including reduction of INHBE mRNA and Activin E protein, a lipolysis suppressor that is upregulated in obesity. Liver INHBE mRNA was strongly correlated with serum Activin E levels following INHBE-siRNA treatment.
• A single dose of INHBE-siRNA led to weight loss on par with semaglutide.
  • There was a decrease in diet-induced visceral adipose mass and shrinkage of adipocytes compared with PBS treatment, supporting the restoration of healthy adipose tissue with this mechanism of action. Muscle mass was preserved.
  • Infiltration of activated macrophages in visceral adipose was significantly decreased by a single dose of INHBE-siRNA compared with PBS controls. INHBE-siRNA also significantly reduced proinflammatory M1 macrophage (CD11c positive) recruitment while sustaining levels of anti-inflammatory M2 macrophages in visceral fat, indicating an overall shift away from a pro-inflammatory state.
• When administered as an add-on to semaglutide, a single dose of INHBE-siRNA doubled the amount of weight loss, highlighting potential for combination treatment.
• Wave’s INHBE siRNA curtailed rebound weight gain when semaglutide treatment was discontinued, highlighting its potential as an off-ramp and maintenance treatment following GLP-1 treatment.
  
  

The full presentation can be accessed by visiting “Scientific Presentations” on the Investors section of the Wave Life Sciences website: https://ir.wavelifesciences.com/events-publications/scientific-presentations.

About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM^®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy, Huntington’s disease, and Obesity, as well as several preclinical programs utilizing the company’s broad RNA therapeutics toolkit. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) and LinkedIn.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding our expectations for WVE-007 and the anticipated therapeutic benefits thereof; the anticipated timing of clinical data from our INLIGHT clinical trial of WVE-007; the novelty of our approach to silence INHBE mRNA in order to achieve healthy, sustainable weight loss and the potential for once- or twice-yearly dosing; the potential benefits of WVE-007 over existing obesity therapies; the potential of WVE-007’s mechanism (INHBE) as a novel and unique obesity treatment to induce fat loss, preserve muscle, and drive weight loss;  our understanding of our preclinical data for WVE-007 and our expectations of how such data will translate in humans; beliefs that Wave’s portfolio of RNA medicines is differentiated, potentially best-in-class and potentially transformative; the broad potential of Wave’s RNA medicines pipeline and oligonucleotide chemistry and any benefits that may arise as a result thereof. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release and actual results may differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as amended, and in other filings Wave makes with the SEC from time to time. Wave undertakes no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances.

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