Lead oral compounds demonstrated up to 25% body weight reduction with preferential fat loss, preserved lean mass, and broad metabolic improvements in DIO models
BOSTON, June 25, 2026 /PRNewswire/ -- Mwyngil Therapeutics, a biotech company focused on developing innovative small molecule therapeutics for cardiometabolic disease, today announced positive in vivo proof-of-concept results from its GPR75 inverse agonist program, supporting the potential of GPR75 modulation as a differentiated therapeutic approach for obesity and cardiometabolic disease. In a 4-week, diet-induced obesity (DIO) mouse model, orally administered lead compounds produced dose-dependent body weight reduction of up to 25% versus vehicle while preserving lean mass across all tested doses. Importantly, weight reduction was accompanied by preferential loss of adipose tissue rather than muscle, with a 33–50% reduction in fat rate and up to 1.5-fold reduction in epididymal white adipose tissue (eWAT). Additional in vivo findings demonstrated broad metabolic improvements beyond body weight reduction, including:
- Ameliorated glycemic control with reductions in fasting blood glucose and HbA1c
- Reductions of systemic inflammatory markers, including CRP and IL-18
- Reduced liver weight and improvement of hepatic and lipid biomarkers including ALT/AST and LDL/total cholesterol
"These data suggest that GPR75 inverse agonism may offer a differentiated obesity profile focused on quality weight loss rather than weight reduction alone," said Luba Greenwood, CEO of Mwyngil Therapeutics. "We observed robust body weight reduction together with preservation of lean mass and improvements across multiple metabolic parameters, supporting the broader role of GPR75 in systemic metabolic regulation."
The program builds on strong human genetic validation of GPR75. A large human genetics study involving approximately 640,000 individuals identified loss-of-function variants in GPR75 associated with lower BMI and reduced obesity risk. In parallel, GPR75 knockout mice demonstrated substantially reduced susceptibility to diet-induced weight gain.
Mwyngil's compounds were developed as selective oral allosteric inverse agonists designed to modulate central metabolic regulatory pathways. Lead molecules demonstrated functional potency in the lower double-digit nanomolar range in a cell-based β-arrestin assay and showed favorable selectivity and developability characteristics. Oral exposure and brain penetration were consistent with central target engagement.
Unlike mechanisms primarily driven by appetite suppression, Mwyngil's approach is designed to influence central energy homeostasis through modulation of GPR75 signaling, a pathway genetically linked to obesity and metabolic disease. The company is continuing optimization of the program and expects to advance a development candidate following completion of ongoing translational and preclinical activities.
About Mwyngil Therapeutics
Mwyngil Therapeutics is developing first-in-class oral small molecule therapies targeting genetically validated pathways in obesity and cardiometabolic disease. The company's GPR75 program is focused on delivering clinically meaningful weight reduction while preserving lean mass and improving broader metabolic health outcomes. Other programs in development include brain penetrant molecules targeting PTP-1B and NLRP3.
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SOURCE Mwyngil Therapeutics
