SUN-664 SYNT-101: First-in-Human Evaluation of a Novel Pharmacologic Therapeutic to Replicate Gastric Bypass for Management of Obesity

Abstract Disclosure: M. Hudson: Syntis Bio. L. Sandoval: Syntis Bio. P.D. Susilo: Syntis Bio. D. Sim: Syntis Bio. M. Buzo Pena: Syntis Bio. S. Pizzo: Syntis Bio. D. Ezekoye: None. A. Maheshwari: None. S. Cho: None. R. Sharma: None. M. Lanchantin: Syntis Bio. S. Zale: None. G. Traverso: Syntis Bio. R. Langer: Syntis Bio. R. Dhanda: Syntis Bio. V. Sethuraman: Syntis Bio. Background: SYNT-101 is a novel, orally administered therapeutic designed to treat obesity by establishing a tissue lining to redirect nutrient absorption past the proximal to the distal bowel. It has shown promising effects on glycemic control in multiple animal models and has demonstrated effective weight reduction and lean mass preservation in diet-induced obesity (DIO) rodent models. In this study, we present SYNT-101 first-in-human data, highlighting its safety, efficacy, and solid dosage form development. Methods: Nine healthy subjects (2 male, 7 female), aged 24 to 53 years with a BMI ranging from 19 to 29, received a single dose of SYNT-101 in a suspension formulation across multiple doses. The cohort was divided into three groups based on dosage: 25% (n=2), 50% (n=3), and 100% (n=4) of the target SYNT-101 level. Comprehensive safety assessments and oral glucose tolerance tests (OGTT) were performed to confirm SYNT-101 safety and efficacy. Endoscopic imaging was used to characterize duodenal surface coverage spatially and temporally. Plasma samples were collected to assess the impact on satiety/metabolic hormone levels (liver enzymes, leptin, ghrelin). Results: Endoscopic imaging revealed extensive SYNT-101 coverage throughout the duodenum. Safety assessments showed no adverse or serious adverse events in any treatment group. Per individual, liver enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, remained unchanged over a ten-day period post-treatment. Gastrointestinal tolerance was excellent, with no changes observed in the Gastrointestinal Symptom Rating Scale (GSRS) and an average pain rating of 0 (n=9). Histopathological examinations conducted 24 hours post-administration showed normal duodenal mucosa, with no signs of erosion or residual SYNT-101. OGTT tests demonstrated delayed glucose absorption with SYNT-101 treatment. After SYNT-101 administration, there was an average 34.7% reduction in the area under the curve within the first 30 minutes and a 20.9% reduction within 60 minutes, suggesting nutrient redirection from the duodenum to later in the intestine. Consistent with reduced food intake in the pre-clinical in vivo models, 100% of patients tested exhibited elevated plasma leptin levels and reduced ghrelin. Furthermore, we have shown enhanced coverage and reduced variability in OGTT by developing an orally delivered solid dosage formulation. Conclusions: SYNT-101 has demonstrated a strong profile of safety, tolerability, and efficacy in first-in-human studies, showing promise as a well-tolerated therapeutic option for effective weight loss solutions. Unlike many existing treatments, SYNT-101 offers a safe, tolerable, and effective oral alternative to current injectable and/or systemic therapies for weight management. Presentation: Sunday, July 13, 2025