SYNT-101 once-daily oral treatment for obesity mimics RYGB

Syntis Bio has announced positive preclinical and first-in-human data for its lead candidate, SYNT-101, an investigational once-daily oral treatment for obesity. The data were presented at the European Congress on Obesity and Weight Management (Obesity 2025) in Barcelona.

SYNthetic Tissue-lining (Credit: Syntis Bio

SYNT-101 is being developed as a once-daily pill for the treatment of obesity. It works by transiently blocking nutrient absorption in the duodenum, the upper part of the small intestine, and redirecting nutrients to the distal small intestine to stimulate the natural secretion of satiety and metabolism-regulating hormones, including GLP-1. According to the company, this mechanism, known as duodenal nutrient exclusion, is a key contributor to the efficacy of gastric bypass surgery, which remains the gold standard for weight loss and metabolic disease management. SYNT-101 leverages the power of SYNT (SYNthetic Tissue-lining), an oral formulation that establishes a safe, transient polymer coating to the duodenum.

SYNT-101 is designed to induce metabolic changes that support improved glycaemic control, weight loss and energy balance by redirecting nutrient absorption from the proximal to distal small intestine, creating a similar effect to gastric bypass.

In preclinical rodent models, SYNT-101 produced consistent 1% weekly weight loss over the six-week study period while preserving 100% of lean muscle mass. In a first-in-human pilot study, an investigational formulation of SYNT-101 demonstrated strong evidence of nutrient redirection and resulting satiety hormone modulation. Importantly, SYNT-101 displayed strong safety and tolerability across both studies, with no adverse events reported.

“These data further validate the potential of SYNT-101 as a convenient once-daily oral alternative or complement to GLP-1 drugs, which often involve substantial costs, severe side effects such as muscle loss and long-term maintenance issues despite high efficacy rates,” said Rahul Dhanda, chief executive officer of Syntis. “With SYNT-101, we believe we can deliver sustainable, safe, effective weight loss by reducing fat while preserving lean muscle and stimulating natural production of satiety hormones, including GLP-1, to prevent weight regain. We are excited to replicate and expand upon these promising data in our upcoming Phase 1 clinical trial.”

The first presentation, ‘SYNT-101 first-in-human evaluation of a novel pharmacologic therapeutic to replicate gastric bypass for management of obesity’, summarises data from a nine-person safety and tolerability study of the drug at three dose levels. No treatment-related adverse events were reported, and all biopsy samples showed normal tissue histology. Glucose tolerance testing confirmed effective nutrient diversion, with no changes in safety biomarkers and complete clearance within 24 hours. Additionally, participants demonstrated favourable acute postprandial shifts in appetite-regulating hormones, including increased leptin and decreased ghrelin, consistent with enhanced satiety signalling and metabolic regulation.

The company also discussed data from a six-week study of diet-induced obesity rodent models in a second presentation, ‘Preclinical evaluation of SYNT-101: effects on glycaemic control, weight loss and body composition in obese rodents’. Following daily dosing and compared to control rodents, the test subjects experienced a total average weight loss of 6.1% (1% per week), 10% reduction in caloric consumption and 8% decrease in fasting glucose levels. Notably, lean muscle mass was fully preserved throughout the study, and no adverse events were observed.

“The safety profile that SYNT-101 has shown to date, coupled with these data demonstrating preservation of lean muscle mass, is remarkable and an important advance in today’s obesity treatment landscape,” commented Dr Louis Aronne, obesity expert, past president of The Obesity Society, and member of the Syntis clinical advisory board. “A major pitfall of current GLP-1 drugs is related to the gastrointestinal side effects as well as the loss of lean muscle that accompanies weight loss. Based on these data, SYNT-101’s mechanism of action may avoid these issues entirely, which could provide both an alternative and adjunct for the millions of people living with obesity.”

Syntis plans to submit an investigational new drug (IND) application to the FDA later in 2025.