Wave Life Sciences is making strides in developing RNA-based therapies for obesity and cardiometabolic diseases. The company highlighted its progress, including the upcoming clinical trial for WVE-007, an INHBE-targeting GalNAc-siRNA for obesity, slated to begin in the first quarter of 2025. Additionally, Wave introduced new RNA editing programs aimed at addressing unmet needs in cardiometabolic disorders.
WVE-007: A Novel Approach to Obesity Treatment
WVE-007 represents a novel approach to obesity treatment by targeting INHBE, a gene linked to healthier cardiometabolic profiles in individuals with loss-of-function mutations. These individuals typically exhibit less visceral fat, lower triglycerides, and a reduced risk of type 2 diabetes and cardiovascular disease. Preclinical data in diet-induced obese (DIO) mice indicate that WVE-007 can directly impact adipocytes, inducing lipolysis, which differs from the mechanism of GLP-1s that primarily affect appetite through the digestive and central nervous systems.
The planned Phase 1 clinical trial will assess the safety, tolerability, pharmacokinetics, and target engagement of WVE-007 in overweight or obese adults. The trial will also evaluate changes in body composition. According to Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences, WVE-007 "reimagines obesity treatment with a mechanism that directly impacts fat cells – particularly visceral fat – and which could be used as monotherapy, add-on to GLP-1s, or for maintenance post-GLP-1 cessation."
Expanding RNA Editing Capabilities for Cardiometabolic Diseases
Building on its RNA editing capabilities demonstrated with WVE-006 in alpha-1 antitrypsin deficiency, Wave Life Sciences is expanding its focus to cardiometabolic diseases. Three new wholly owned RNA editing programs targeting PNPLA3, LDLR, and APOB are on track for candidate selection in 2025. These programs leverage GalNAc conjugation for efficient clinical paths to proof-of-concept.
- PNPLA3 (mRNA correction): Aims to correct the PNPLA3-I148M mutation, which is associated with a high risk of liver diseases. The goal is to achieve at least 50% correction to restore the heterozygous phenotype, similar to the approach used with WVE-006. There are over 9 million impacted individuals in the US and Europe.
- LDLR (mRNA upregulation) and APOB (mRNA correction): Targets familial hypercholesterolemia (FH) patients who do not reach target LDL-c levels with current therapies. Wave’s AIMers are designed to upregulate LDLR and correct APOB, potentially offering first-in-class treatments for heterozygous FH (HeFH) patients. These AIMers could address approximately 1 million HeFH patients in the US and Europe. LDLR upregulation also presents opportunities in patients with statin intolerance or prior cardiovascular events, representing a patient population of around 30 million in the US and Europe.
Advancements in Chemistry for Intracellular Delivery
Wave Life Sciences also highlighted advancements in its proprietary chemistry, which enhances intracellular delivery in five key areas: cellular uptake, endosomal release, cellular residency, nuclear uptake, and target engagement. The company is utilizing PN variants and modifications to physicochemical properties to improve siRNA silencing and RNA editing in extrahepatic tissues. Novel chemistry, including proprietary N-3-uridine chemistry (N3U), substantially enhances RNA editing efficiency, as detailed in a recent publication in Nucleic Acids Research.
